Role of Electron-Deficient Olefin Ligands in a Ni-Catalyzed Aziridine Cross-Coupling to Generate Quaternary Carbons

Cross-Coupling To Generate Quaternary Carbons

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Role of Electron-Deﬁcient Oleﬁn Ligands in a Ni-Catalyzed Aziridine

Jesus G. Estrada, Wendy L. Williams, Stephen I. Ting, and Abigail G. Doyle*

Cite This: https://dx.doi.org/10.1021/jacs.0c02237

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sı Supporting Information

ABSTRACT: We previously reported the development of an

electron-deﬁcient oleﬁn (EDO) ligand, Fro-DO, that promotes

the generation of quaternary carbon centers via Ni-catalyzed Csp −

Csp cross-coupling with aziridines. By contrast, electronically and

structurally similar EDO ligands such as dimethyl fumarate and

electron-deﬁcient styrenes aﬀord primarily β-hydride elimination

side reactivity. Only a few catalyst systems have been identiﬁed that

promote the formation of quaternary carbons via Ni-catalyzed

Csp −Csp cross-coupling. Although Fro-DO represents a promis-

ing ligand in this regard, the basis for its superior performance is not

well understood. Here we describe a detailed mechanistic study of

the aziridine cross-coupling reaction and the role of EDO ligands in

0/II

cycle with a Ni^I^I

facilitating Csp −Csp bond formation. This analysis reveals that cross-coupling proceeds by a Ni

azametallacyclobutane catalyst resting state. Turnover-limiting C−C reductive elimination occurs from a spectroscopically

observable Ni -dialkyl intermediate bound to the EDO. Computational analysis shows that Fro-DO accelerates turnover limiting

reductive elimination via LUMO lowering. However, it is no more eﬀective than dimethyl fumarate at reducing the barrier to Csp −

Csp reductive elimination. Instead, Fro-DO’s unique reactivity arises from its ability to associate favorably to Ni intermediates.

Natural bond order second-order perturbation theory analysis of the catalytically relevant Ni intermediate indicates that Fro-DO

binds to Ni through an additional stabilizing donor−acceptor interaction between its sulfonyl group and Ni . Design of new ligands

to evaluate this proposal supports this model and has led to the development of a new and tunable ligand framework.

INTRODUCTION

1B). EDOs have also been shown to accelerate reductive

elimination, arising from the ligand’s ability to stabilize the

buildup of electron density on the metal center in the

■

Transition-metal-catalyzed cross-coupling has emerged as the

prevailing method for C−C bond formation in a wide range of

subdisciplines of chemistry, from medicinal and process

transition state. Oleﬁn binding may also accelerate reductive

elimination through generation of an odd-coordinate complex

that undergoes reductive elimination faster than a correspond-

chemistry to materials science. While most applications

involve Csp −Csp cross-coupling, remarkable advances have

been described for Csp −Csp and Csp −Csp bond

formation. Nevertheless, Csp −Csp cross-coupling remains

a considerable challenge, particularly when generating

quaternary carbon centers. The comparative lack of success

in these cross-coupling reactions can be attributed to a few

factors. Reductive elimination is slow because it proceeds from

a directional sp -orbital and incurs high reorganizational energy

during the bond-forming step. Additionally, the alkyl metal

intermediate may undergo reversible β-hydride elimination

followed by facile C−H reductive elimination, resulting in the

overall reduction or isomerization of substrates (Figure 1A).

The use of electron-deﬁcient oleﬁns (EDOs) as ligands in

ing even-coordinate complex. In the context of Csp −Csp

bond formation with Ni, Yamamoto was ﬁrst to study the

impact of oleﬁnic ligands on reductive elimination, using

(bipy)NiEt complexes as model substrates (Figure 1C).

Subsequently, Knochel deployed these ligands in catalysis,

demonstrating a Ni-catalyzed Negishi Csp −Csp cross-

coupling of primary alkyl electrophiles. In this case, inclusion

of an electron-deﬁcient styrene led to improved product

selectivity over side products that are formed in the ligand’s

absence. These studies set the stage for the application of

Received: February 28, 2020

Csp cross-coupling reactions has emerged as a successful

approach to address challenges associated with slow reductive

elimination and facile β-hydride elimination. These π-

deﬁcient ligands have been proposed to serve multiple roles.

EDOs can improve product selectivity by deterring β-hydride

elimination through occupation of a coordination site (Figure

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Figure 1. Electron-deﬁcient oleﬁn (EDO) ligands in Ni-catalyzed Csp cross-coupling reactions.

simple fumarate and styrene derivatives as ligands in a range of

Ni-catalyzed Csp cross-coupling reactions, including a 2012

Motivated by the eﬃciency of this reaction system for

quaternary carbon C−C bond formation and the unexplained

diﬀerence in reaction outcome between Fro-DO and the other

π-deﬁcient ligands, we undertook a detailed investigation of the

aziridine cross-coupling reaction. Here, we describe kinetic,

spectroscopic, and computational studies aimed at elucidating

its mechanism and the structural features of EDOs responsible

for reactivity and selectivity. We present evidence that a Fro-

study from our group investigating a Ni-catalyzed Negishi

Csp −Csp cross-coupling of styrenyl aziridines in which

dimethyl fumarate was necessary to accomplish Csp −Csp

1,12

bond formation.

In 2015, our group reported a Ni-catalyzed Negishi cross-

coupling reaction with 2,2-disubstituted aziridines as electro-

philes using a novel EDO ligand, Fro-DO (Scheme 1). This

DO-bound Ni azametallacyclobutane is the resting state of

the catalyst and that Fro-DO-promoted Csp −Csp reductive

elimination is the turnover-limiting step. On the basis of

computational studies and structure−activity relationships, we

ﬁnd that the feature that distinguishes Fro-DO from other

Scheme 1. Ni-Catalyzed Negishi Csp −Csp Cross-coupling

of 2,2-Disubstituted Aziridine 1 Exhibits Diﬀerent

Selectivity among EDOs

oleﬁnic ligands is its ability to coordinate favorably to Ni

intermediates via its sulfonyl group. This surprising insight

enabled us to redesign the ligand framework, resulting in a

more synthetically accessible and modular ligand class, one

member of which aﬀords comparable activity to Fro-DO. This

study aﬀords a mechanistic platform for future ligand design

eﬀorts and has resulted in the discovery of a ligand framework

that may prove of broad utility in the development of other

challenging Ni-catalyzed Csp −Csp cross-coupling reactions.

RESULTS AND DISCUSSION

■

Kinetic Analysis. At the outset of this study we considered

two possible catalytic pathways for the reaction, following

/II

I/III

0/II

either a Ni cycle or a Ni cycle (Scheme 2). While Ni

cycles have been proposed for most aziridine cross-coupling

I/III

reactions, a Ni

catalytic cycle is commonly invoked for

^a¹⁹F NMR yields.

diﬃcult alkyl−alkyl cross-coupling reactions since reductive

III

elimination proceeds at a faster rate from Ni than from

II 18,19

reaction represents a rare example of a Ni-catalyzed Csp −

Ni .

Moreover, β-hydride elimination from a Ni -alkyl

Csp cross-coupling reaction that forms quaternary carbon

intermediate is expected to be less favorable than from a more

4−16

centers.

Under the optimized reaction conditions, cross-

electrophilic Ni center. To interrogate these possibilities

coupled product 2 is generated in high yields and high product

selectivity over β-hydride elimination products 3a and 3b.

kinetically, the Negishi cross-coupling of ﬂuorinated aziridine 1

with n-BuZnBr was chosen as the model system (Scheme 1).

We used a combination of Reaction Progress Kinetic Analysis

Notably, dimethyl fumarate and 4-CF -styrene aﬀorded mostly

β-hydride elimination side products 3a and 3b despite their

(RPKA), Bures

’ method of kinetic analysis, initial rate

success as ligands for other Csp −Csp cross-coupling

reactions. Furthermore, reactions run in the absence of ligand

or with other ligand classes delivered no desired cross-coupled

product.

kinetics, and Method of Continuous Variation (MCV) to

study the eﬀect of reaction component concentrations on the

rate of the catalytic reaction. All reactions were monitored

using in situ F NMR.

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

shown in eq 3, the concentration of [2 ] is a function of [1 ]₀

Article

Scheme 2. Possible Catalytic Cycles for the Ni-Catalyzed

Csp −Csp Cross-Coupling Reaction

and [1]. Therefore, the apparent inverse ﬁrst-order depend-

ence on [1]₀is likely a result of an inverse ﬁrst-order

dependence on [2]. This is in agreement with the product

inhibition result observed in the same excess experiment.

Taken together, these data establish that minimal to no catalyst

decomposition occurs over the course of the catalytic

reaction.

Kinetic Rate Orders. Additional diﬀerent-excess experiments

were performed to evaluate each reaction component and to

determine the rate orders in [Ni], [Fro-DO], and [n-BuZnBr].

Variation of the Ni concentration from 4 to 11 mM (3−9 mol

loading), while maintaining the ligand concentration

constant at 12.5 mM, revealed a ﬁrst-order dependence on

25,26

[Ni] (Figure 2E).

To determine the rate order in [Fro-

DO], the concentration of Fro-DO was varied from 4 to 20

mM at constant Ni concentration. We observed saturation

kinetic behavior in [Fro-DO] (Figure 2F). Saturation

kinetics was also observed for the rate dependence on [n-

BuZnBr] (Figure 2G). At synthetically relevant conditions,

[Fro-DO] = 12.5 mM and [n-BuZnBr] = 0.35 M, the reaction

is zero-order in [Fro-DO] and ﬁrst-order in [n-BuZnBr]

suggesting that the catalyst resting state is ligand-bound and

transmetalation occurs after formation of the catalyst resting

state.

Catalyst Decomposition vs Product Inhibition. We began

with the same excess protocol of RPKA, a useful tool to

interrogate catalyst decomposition. We monitored two

catalytic reactions, the standard reaction with an aziridine 1

concentration of 0.125 M and a same excess reaction at

approximately 50% conversion ([1] = 0.065 M). As shown in

Figure 2A, the rate proﬁle of the same excess reaction did not

overlay with that for the standard reaction. Instead, the

standard reaction proceeded at a slower rate, indicating either

catalyst deactivation or product inhibition. To probe these

possibilities, we added product 2 (0.060 M) into the same

Product inhibition and the lack of an NMR handle on the

organozinc reagent made obtaining a rate dependence on [1]

using RPKA diﬃcult. Therefore, we pursued the method of

initial rates by monitoring the ﬁrst 10% conversion of aziridine

1. As shown in Figure 2D, we observed a zero-order

excess reaction. The resulting rate proﬁle overlaid with the

standard reaction, indicative of product inhibition. Product

inhibition was further evaluated using the diﬀerent excess

protocol of RPKA in which the concentration of one reaction

component is varied. While evaluating the reaction rates at

aziridine concentrations in the range 0.065−0.125 M [1], an

dependence on [1] . The lack of rate dependence on [1]

demonstrates that the catalyst resting state of the reaction is an

aziridine-bound Ni complex. Thus, oxidative addition can be

ruled out as the turnover-limiting step of the reaction.

Ni:Fro-DO Stoichiometry. Although our previously reported

catalytic conditions were optimized to a 1:2 ratio of metal to

ligand, the Ni to Fro-DO stoichiometry at the transition state

was determined to be 1:1 (χ _F _r _o _-_D _O = 0.5, Figure 2 H). Taken

inverse ﬁrst-order dependence on [1] was observed (Figure

B). This unexpected observation can be rationalized based on

the graphical rate law (Figure 2C). According to the identity

Figure 2. (A) Same excess experiments. (B) Diﬀerent excess experiments varying [1] . (C) Proposed graphical rate law for product inhibition. (D)

Initial rates kinetic analysis on [1]. Diﬀerent excess experiments varying (E) [Ni], (F) [Fro-DO], (G) [n-BuZnBr]. (H) MCV plot at various mole

moles of Fro‐DO

fixed total moles of Fro‐DO + Ni

fractions of Fro-DO.

Fro‐DO

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Figure 3. ¹⁹F NMR studies (solvent = DMA). (A) Observation of Ni catalytic intermediates and structure determination of Ni intermediate A. (B)

Structure determination of Ni intermediate B.

together with the ﬁrst-order kinetic dependence on [Ni] and

zero-order dependence on [Fro-DO], these results suggest that

there is only one molecule of Fro-DO bound to Ni throughout

the catalytic cycle.

intermediate A in the catalytic reaction was calculated using

an internal standard to be approximately 50% of the total Ni

concentration; A is thus the catalyst resting state. This

observation is consistent with the zero-order rate dependence

on [1]. Furthermore, this experiment provides evidence that an

Spectroscopic Analysis. We turned to spectroscopic

studies to further interrogate the mechanism of the reaction.

oleﬁnic ligand is not required for the oxidative addition step.

The peak for the in situ generated oxidative adduct (spectrum

F NMR studies of the catalytic reaction showed the

appearance of two peaks (δ) at −123.7 ppm (A) and

125.9 ppm (B), which both disappear at the end of the

2) overlaps with that of intermediate A in the catalytic

−

reaction. F NMR is inconclusive, however, in determining

the ligation state of Ni intermediate A. Based on the

observation of zero-order kinetic dependence on [Fro-DO]

reaction or upon exposure to air. The air sensitivity of these

two species is suggestive of Ni intermediates. No signiﬁcant

changes were observed in the concentration of these two

intermediates over the course of reaction, indicating that if

these two species are catalytic intermediates, steady-state

kinetics are achieved and no change in mechanism takes place

and further support by DFT, we propose that intermediate A

is the Fro-DO-bound Ni oxidative adduct.

Ni Intermediate B. Having assigned intermediate A as the

Ni oxidative adduct of aziridine 1, we proceeded to investigate

the minor peak at −125.9 ppm (B). As with intermediate A,

the absence of EPR signals associated with the catalytic

(

Figure 3A).

Ni Intermediate A. The addition of aziridine 1 to Ni(cod)₂

III

(0.5 equiv) in DMA at room temperature causes a gradual

reaction mixture argued against a Ni or Ni oxidation state.

Initially we considered two possible structures for intermediate

B that would result from the reaction of intermediate A with n-

color change from yellow to red over the course of 20 min,

with generation of the peak A observed in the catalytic reaction

(

Figure 3A, spectrum 2). UV−vis spectroscopic analysis of the

BuZnBr. One possibility is a Ni -dialkyl species resulting from

red aziridine 1/Ni(cod) mixture showed an absorption band

at 505 nm (λ ) consistent with a d-d transition of a Ni d -

complex. The assignment of a Ni oxidation state was

transmetalation of intermediate A with n-BuZnBr (Figure 3B).

Alternatively, intermediate B could be a Ni -bromide species

max

arising from ring opening of intermediate A by a bromide ion.

To interrogate these two possibilities, we performed

spectroscopic experiments with distinct organozinc reagents.

By changing the organozinc reagent in the catalytic reaction

supported by electron paramagnetic resonance (EPR) studies

III

of the catalytic reaction mixture, which showed no Ni or Ni

species (Figure S16). The newly formed Ni complex proved

diﬃcult to isolate and decomposed in solution after 20 min.

The unstable complex could, however, be stabilized by

addition and trapping with bipyridine, causing the peak at

from n-BuZnBr to BnZnBr and PhZnBr, we observed

distinguishable changes in the chemical shift of intermediate

B, providing evidence for a Ni -dialkyl intermediate (Figure

−

123.7 ppm to disappear and a new peak at −120.3 ppm to

3B, spectra 1−3). Next, we probed the proposed anionic

nature of the sulfonamide group of Ni intermediate B. Various

bromide salts (0.4 equiv) were added to the catalytic reaction,

and the eﬀect on the chemical shift of intermediate B was

evaluated. Indeed, the chemical shift of intermediate B was

appear (spectrum 3). The new species was assigned as

azametallacyclobutane complex 4 by independent preparation

and NMR characterization of 4 from (bipy)NiEt and 1

according to the procedure from Hillhouse (spectrum 4).

With this structural assignment, the concentration of

sensitive to the identity of the cations (M ) in solution in a

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Article

manner that is consistent with the expected cation Lewis

components, we conclude that the turnover-limiting step of the

catalytic cycle is reductive elimination. Turnover-limiting

reductive elimination is consistent with diﬃcult Csp −Csp

bond formation, especially one involving formation of a

quaternary carbon.

acidity (Li > Na > Zn > [N(n-Bu) ] ) (spectra 4−7).

Finally, consistent with the assignment of intermediate B as the

Ni -dialkyl species, the chemical shift of B remained invariant

whether LiBr or LiCl (0.4 equiv) was added to the catalytic

reaction (spectra 4 and 8).

Elucidation of Ligand Eﬀects. With experimental

evidence establishing turnover-limiting C−C reductive elimi-

Proposed Catalytic Cycle. The kinetic and spectroscopic

I/III

evidence presented above is inconsistent with a Ni catalytic

nation from an oleﬁn-bound Ni -dialkyl intermediate, we

I/III

cycle. First, no Ni

species were observed in the reaction

turned to Density Functional Theory (DFT) to probe the

mixture by EPR. Second, Ni intermediate A, whose structure

was supported by trapping as 4, is formed and consumed under

the catalytic conditions and accounts for the resting state of the

catalyst (Figure 3). Thus, we propose a Ni⁰catalytic cycle,

impact that diﬀerent EDO ligands have on C−C reductive

elimination and association to Ni -dialkyl intermediate B. Two

simpliﬁcations were performed in our DFT studies on the Ni -

/II

dialkyl intermediate: (1) a phenyl group was used instead of

the 4-ﬂuorophenyl group of aziridine 1 and (2) a neutral

sulfonamide group was modeled instead of the anionic

initiated by reduction of Ni(acac) by the organozinc reagent

to form Ni which undergoes rapid oxidative addition to

aziridine 1 to form the azametallacyclobutane intermediate

sulfonamide group. DFT calculations were performed using

a combination of B3LYP/6-31G(d,p) for geometry optimiza-

tions and frequency calculations and M06/6-311+G(d,p) for

single-point energy calculations. Two additional oleﬁns were

included in the DFT analysis in order to elucidate trends: 1-

hexene and fumaronitrile were chosen because they span a

wide range of electron deﬁciency based on LUMO energies.

C−C Reductive Elimination Activation Barrier. We began

our DFT analysis by evaluating the eﬀect of the various oleﬁnic

ligands on the turnover-limiting C−C reductive elimination

(

Scheme 3). The observed saturation kinetic dependence on

Scheme 3. Proposed Catalytic Cycle Based on Kinetic and

Spectroscopic Data (M = ZnBr)

step. Engle and co-workers computationally compared Csp −

Csp reductive elimination from Ni for dimethyl fumarate,

ethylene, and solvent-bound Ni intermediates. To our

knowledge, however, an evaluation of structurally diﬀerentiated

EDOs and their inﬂuence on Csp −Csp reductive elimination

12,36

from Ni has not been performed.

Transition state

structures were computed for the various electronically

diﬀerentiated oleﬁn-bound Ni -dialkyl intermediates and

‡

used to obtain activation barriers (ΔG ). As shown in Figure

A, the highest computed C−C reductive elimination barrier is

‡

for the 1-hexene-bound Ni intermediate (ΔG = 34.4 kcal/

mol). 4-CF -Styrene aﬀords a 4.2 kcal/mol reduction in the

activation barrier (ΔG = 30.2 kcal/mol), consistent with the

‡

ability of π-deﬁcient oleﬁns to lower the barrier of reductive

elimination, though in this case, not to a large enough degree

to enable a synthetically feasible reaction at room temperature.

For Fro-DO- and dimethyl fumarate-bound Ni intermediates,

the barriers are lowered substantially to 23.0 and 23.4 kcal/

mol, respectively. Fumaronitrile exhibits an activation barrier of

14.4 kcal/mol, but under experimental conditions this ligand is

subject to decomposition pathways that make it intractable.

Notably, C−C reductive elimination activation barriers appear

to be largely governed by the electronic properties of the

oleﬁn, as illustrated by the correlation between the LUMO

energy and activation barrier shown in Figure 4A. On this basis

alone, DFT predicts that Fro-DO and dimethyl fumarate

should be of comparable activity since the two ligands have

similar LUMO energies (Figure 4B). However, this is

inconsistent with the disparate yields observed in the catalytic

reaction.

Fro-DO indicates that association of Fro-DO to the Ni^I^I

oxidative adduct is fast and reversible favoring ligated Ni

intermediate A under synthetically relevant conditions. The

oleﬁn-bound oxidative adduct A undergoes transmetalation

with n-BuZnBr to aﬀord intermediate B, both of which were

observed spectroscopically under the reaction conditions (A:B

≈

3.5:1). While the ﬁrst-order dependence on organozinc

could support a turnover-limiting transmetalation, we discount

this possibility based on the observation of post-trans-

metalation intermediate B. Thus, the data support a turn-

over-limiting reductive elimination from intermediate B to

provide cross-coupled product 2−ZnBr bound to a regen-

Oleﬁn Association. Alternatively, we considered that oleﬁn

association to the Ni -dialkyl intermediate may give rise to the

diﬀerences in reaction outcome. Tolman has previously

investigated the association of oleﬁnic ligands to Ni

erated Ni . Ni sequestered by product 2 accounts for the

experimentally and found that log(K) correlates with oleﬁn

24b

product inhibition observed in the reaction. Based on the

E_L_U_M_O. While this would not be expected to diﬀerentiate Fro-

spectroscopic evidence for oxidative adduct A and Ni -dialkyl

DO from dimethyl fumarate given the similarity in their E

energies, these studies were conducted with Ni and a similar

LUMO

intermediate B, as well as the rate orders for all reaction

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Figure 5. (A) Free energies change (ΔG) for oleﬁn association to a

Ni -dialkyl intermediate, corrected to account for concentrations

under synthetically relevant conditions. (B) Plot of ΔG vs oleﬁn

. (C) Product distribution at diﬀerent loadings of dimethyl

LUMO

fumarate.

Figure 4. (A) C−C reductive elimination activation barriers vs oleﬁn

LUMO energy (computed at the M06 level of theory). (B) π-

Backbonding and reductive elimination barriers do not explain the

diﬀerential performance of dimethyl fumarate and Fro-DO.

nation with the aziridine-derived methyl group, generating side

product 3b′ (ΔG = 19.7 kcal/mol). The relative barriers of β-

‡

hydride elimination and C−C reductive elimination are

consistent with the fact that Fro-DO provides predominantly

desired product while dimethyl fumarate provides predom-

inantly undesired β-hydride elimination products. As discussed

above, this distinction arises from Fro-DO’s stronger

association to intermediate B, rather than a lower barrier for

reductive elimination.

investigation has not been conducted with Ni . Thus, we

continued the head-to-head comparison between the oleﬁnic

ligands by evaluating their association behavior to Ni . More

speciﬁcally, the Gibbs free-energy changes (ΔG) for oleﬁn

association to the solvent-bound Ni intermediate B were

computed and are shown in Figure 5A−B. These values are

corrected to account for the concentrations of all species under

synthetically relevant conditions (see Supporting Information).

Similar to the trend observed by Tolman and for the C−C

reductive elimination activation barriers in Figure 4A, oleﬁn

To experimentally evaluate these DFT studies, we posited

that it should be possible to improve product selectivity with

dimethyl fumarate simply by increasing its concentration to

favor the oleﬁn-bound Ni intermediate since the ligand is

predicted by DFT to substantially reduce the barrier to C−C

‡

reductive elimination (ΔG = 23.0 kcal/mol). In contrast, the

association to the Ni -dialkyl intermediate was found to

computational analysis suggests that 4-CF -styrene should not

‡

correlate with LUMO energies of the free oleﬁn. Binding of the

simple oleﬁnic ligands exhibits ΔG values ranging from 4.6

kcal/mol for 1-hexene to 0.5 kcal/mol for fumaronitrile.

However, Fro-DO does not follow the expected trend and

DFT predicts a large negative free-energy change for its

association (ΔG = −6.8 kcal/mol), favoring the oleﬁn-bound

be a competent ligand (ΔG = 30.2 kcal/mol), independent of

its concentration. Thus, we evaluated the yield of cross-

coupled product 2 and β-hydride elimination products 3a and

3b at higher loadings of both dimethyl fumarate and 4-CF₃-

styrene. As the loading of dimethyl fumarate was increased

from 10−50 mol %, we observed an increase in yield of cross-

coupled product 2 accompanied by an equal decrease in the

yields of β-hydride elimination products 3a and 3b (Figure

5C). At approximately 50 mol % loading, the catalytic reaction

is saturated in dimethyl fumarate ultimately achieving a 1:1

selectivity of cross-coupled to combined β-hydride elimination

Ni intermediate. These results identify the diﬀerence

between Fro-DO and dimethyl fumarate as originating from

its ability to coordinate favorably to the Ni -dialkyl

intermediate B by approximately 9 kcal/mol.

The observed selectivity for cross-coupled product vs β-

hydride elimination side products can be understood from

Figure 6, which depicts the overall energy landscape.

Regardless of what EDO is present, the β-hydride elimination

side products 3a and 3b are envisioned to form via the same

coordinatively unsaturated Ni intermediate. This intermediate

can undergo β-hydride elimination with the n-Bu group

products. Use of 4-CF -styrene however led to full

conversion of starting material without any appreciable yield

of cross-coupled product 2 (<5% F NMR yield) even at 100

mol % loading. These experimental results provide support for

the DFT analysis and indicate that the primary diﬀerence

between Fro-DO and dimethyl fumarate originates in

followed by C−H reductive elimination to form side product

association to Ni .

‡

a′ (ΔG = 17.1 kcal/mol (Figures 6, S32). Alternatively, the

Ni:Fro-DO Interactions. The binding of the simple oleﬁns to

unsaturated Ni intermediate can undergo β-hydride elimi-

the Ni -dialkyl intermediate is largely dictated by Ni π-

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

square-planar complex (Figure 7 ). In order to probe this

Figure 6. Energy landscape for formation of desired C−C reductive elimination products and undesired β-hydride elimination products. 3a′ and

b′ refer to the desﬂuoro versions of 3a and 3b. The barrier shown leading to 3a′ is for the C−H reductive elimination following β-hydride

elimination of the n-Bu group (see Figure S32 ).

backbonding interactions as described by the Dewar−Chatt−

therefore set out to interrogate this eﬀect experimentally

through the use of structure−activity relationships. We

envisioned modifying Fro-DO’s structure by replacing the

methylene proximal to the sulfonyl group with a N−R group

(Figure 8A). This modiﬁcation to the ligand framework would

allow the facile installment of a variety of N-substituents that

we expected would impact the Lewis basicity of the sulfonyl

group while having minimal inﬂuence on the oleﬁn LUMO

energy.

Data Collection. A simple three-step sequence (see

Supporting Information Section X ) aﬀorded 9 new ligands

with sterically and electronically diﬀerentiated alkyl, benzyl,

and aryl groups at the sulfonamide nitrogen. The new ligands

were tested in the aziridine cross-coupling reaction and found

to exhibit large reactivity diﬀerences with a range in the yield of

Duncanson model. Strong Ni−oleﬁn bonds are observed

with π-deﬁcient oleﬁns characterized by low-lying LUMO

energies. Fro-DO’s association to Ni, however, is not solely

governed by Ni π-backbonding since Fro-DO and dimethyl

fumarate have similar LUMO energies, yet Fro-DO exhibits

oleﬁn association behavior that is approximately 9 kcal/mol

lower in energy. A closer look at the computed geometry of the

Fro-DO-bound Ni intermediate reveals a potential explan-

ation for the unexpected favorability of Fro-DO association.

One of Fro-DO’s sulfonyl groups is in close proximity to Ni

(

Ni−O = 2.40 Å) resembling an axial ancillary ligand for the

from 11% (R = Me) to 72% (R = Cyp). One of the ligands

bearing a highly electron-deﬁcient group (R = 4-CF -Ph) failed

to provide any appreciable yield of 2 (<5% F NMR yield).

Geometry optimized structures for the oleﬁn-bound Ni

intermediates were then obtained by DFT for each of the

synthesized ligands in the set. This was followed by an NBO

second-order perturbation theory analysis to obtain the

sulfonyl oxygen−Ni interaction stabilization energy. The

delocalization energies and the Ni−O distances are shown in

Figure 8B. Since the delocalization energy largely depends on

how far apart the two interacting species are, a linear

Figure 7. Ground state structure of the Fro-DO-bound Ni -dialkyl

intermediate. Only half of Fro-DO is shown in the inset.

correlation was observed between E(2) and the Ni−O distance

(

R = 0.98). For comparison, E

of the free ligands were

LUMO

also computed.

Linear Regression. Modeling the 8 new ligands that

delivered cross-coupled product 2 and Fro-DO led to the

positive univariate linear correlation between the computed

interaction, we performed a second-order perturbation theory

analysis as carried out in a Natural Bond Order (NBO)

calculation. Indeed we found a donor/acceptor interaction

between one of the sulfonyl oxygen lone pairs and an empty p-

orbital on Ni with a computed E(2) delocalization energy of

E(2) and the yield of 2 (R = 0.80, Figure 8C). Highly

stabilizing secondary interactions arising from electron-rich

sulfonyl groups trend with high yields of cross-coupled product

as expected from the DFT-derived hypothesis but counter-

intuitive according to the traditional view of the role of EDOs

(more electron deﬁcient is more eﬀective). On the other hand,

2.3 kcal/mol.

Linear Regression Analysis. Based on the second-order

perturbation theory analysis of the Fro-DO-bound Ni

intermediate, coordination of Fro-DO’s sulfonyl group to

Ni provides a highly stabilizing secondary interaction. We

a poor correlation was observed (R = 0.26) between the yield

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

https://pubs.acs.org/doi/10.1021/jacs.0c02237.

Article

strong Ni π-backbonding and a secondary interaction between

the ligand’s sulfonyl group and Ni . Structure−activity

relationships within a new EDO-ligand framework provide

experimental evidence of this secondary Ni−oleﬁn interaction.

This insight thus lays a path for mechanism-driven improve-

ment of catalytic activity and applications of the ligand class to

other challenging cross-coupling reactions.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

X-ray crystal structure of L2 R = i-Pr Ligand (CIF)

Experimental procedures, computational data, and

characterization and spectral data for new compounds

(PDF)

AUTHOR INFORMATION

Corresponding Author

■

Abigail G. Doyle − Department of Chemistry, Princeton

University, Princeton, New Jersey 08544, United States;

orcid.org/0000-0002-6641-0833; Email: agdoyle@

princeton.edu

Authors

Jesus G. Estrada − Department of Chemistry, Princeton

University, Princeton, New Jersey 08544, United States;

orcid.org/0000-0001-9578-6912

Wendy L. Williams − Department of Chemistry, Princeton

University, Princeton, New Jersey 08544, United States;

orcid.org/0000-0003-2227-0856

Stephen I. Ting − Department of Chemistry, Princeton

University, Princeton, New Jersey 08544, United States;

orcid.org/0000-0002-6146-8112

Figure 8. (A) Redesigned ligand framework to interrogate the

structural basis for reactivity. (B) Impact of ligand structure on the

yield of 2 (conditions as noted in Scheme 1) and corresponding

calculated Ni−O bond distance, E(2), and E_L_U_M_O. (C) Linear

regression analysis.

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.0c02237

Notes

The authors declare no competing ﬁnancial interest.

of 2 and the oleﬁn LUMO energies consistent with our

hypothesis. The 4-CF -phenyl ligand was not included in the

ACKNOWLEDGMENTS

Dedicated to Professor Eric N. Jacobsen on the occasion of his

0th birthday. The authors gratefully acknowledge Dr. Dennis

C.-Y. Huang and Sonya Karchesmkiy for helpful advice;

Professor Matthew Sigman for guidance on performing

model, since we expect that any product formation arises from

a background reaction. Nevertheless, the computed E(2) value

of 1.9 kcal/mol agrees with the hypothesis that a ligand lacking

this stabilizing secondary interaction fails to deliver cross-

coupled product despite having a LUMO energy that is lower

than that of Fro-DO.

■

multivariate linear regression; Dr. Istvan Pelczer and Kenith

Conover for NMR assistance; and Phillip Jeﬀrey for obtaining

an X-ray crystal structure. Financial support was provided by

NIGMS (R35 GM126986).

CONCLUSION

■

We have performed a mechanistic investigation of a Ni-

catalyzed cross-coupling reaction of 2,2-disubstituted aziridines

requiring the use of an EDO ligand. A series of kinetic and

spectroscopic analyses provide evidence for turnover-limiting

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(

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(

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42) (a) In our original report we provided evidence against sulfonyl

coordination after observing that the sulfonyl groups of Fro-DO were

more than 4 Å from the Ni center in an X-ray crystal structure of

Ni(cod)(Fro-DO). However, sulfonyl coordination should be more

favorable for a Ni species than a Ni . (b) DFT predicts that the

sulfonyl−Ni interaction strengthens in the C−C reductive elimination

transition state where the Ni−O distance is shortened to 2.06 Å.