Computational and Experimental Study of Turbo-Organomagnesium Amide Reagents: Cubane Aggregates as Reactive Intermediates in Pummerer Coupling

Accepted Article

Title: Computational and Experimental Study of Turbo-

Organomagnesium Amide Reagents: Cubane Aggregates as

Reactive Intermediates in Pummerer Coupling

Authors: Ferran Planas, Stefanie V. Kohlhepp, Genping Huang,

Abraham Mendoza, and Fahmi Himo

This manuscript has been accepted after peer review and appears as an

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content of this Accepted Article.

To be cited as: Chem. Eur. J. 10.1002/chem.202004164

Link to VoR: https://doi.org/10.1002/chem.202004164

01/2020

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Chemistry - A European Journal

Computational and Experimental Study of Turbo-

Organomagnesium Amide Reagents: Cubane Aggregates

as Reactive Intermediates in Pummerer Coupling

Ferran Planas,^†Stefanie V. Kohlhepp,^†Genping Huang,^§Abraham Mendoza,^†* and Fahmi

Himo^†*

^†Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91

Stockholm, Sweden

^§Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R.

China

Corresponding authors: Fahmi.Himo@su.se , Abraham.Mendoza@su.se

Abstract

The dynamic equilibria of organomagnesium reagents are known to be very complex, and the

relative reactivity of their components is poorly understood. Herein, a combination of DFT

calculations and kinetic experiments is employed to investigate the detailed reaction

mechanism of the Pummerer coupling between sulfoxides and turbo-organomagnesium

amides. Among the various aggregates studied, unprecedented heterometallic open cubane

structures are demonstrated to yield favorable barriers through a concerted anion-anion

coupling / S–O cleavage step. Beyond a structural curiosity, these results introduce open

cubane organometallics as key reactive intermediates in turbo-organomagnesium amide

mixtures.

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Introduction

Main group organometallics are the most common source of nucleophilic carbon in organic

synthesis. Grignard reagents (R-MgX; 1) have been particularly instrumental due to their

balanced reactivity, cost, and functional group tolerance.¹Structural studies in the solid-state

and solution dynamics of these seemingly simple organometallics have demonstrated the

complexity of their aggregation equilibria, often involving various species co-existing in

solution (Scheme 1A).^2,3The Schlenk-equilibrium yields diorganomagnesium species 2 and it

is an important example of this dynamic behavior, which is influenced by concentration,

solvent, steric properties of the carbon fragment, halide anion, and temperature.^4,5The presence

of magnesium or lithium salts fundamentally changes the reactivity of Grignard reagents and

affects the positions of these equilibria through the formation of mono- or multinuclear

complexes with variable relative stabilities and reactivities (i.e. “linear” dimers 1a, LiCl

adducts 1b, “ate” complexes 1c, open cubane aggregates 1d, etc.).^3,6Despite the studies on the

solution equilibria of these systems to determine the most abundant species in different

conditions, their relative contributions to the overall reactivity is difficult to assess. This is due

to the problematic deconvolution of the roles that various aggregates take in the overall kinetic

progress of the reaction.

The solution equilibria of magnesium amide bases (R₂N–MgX), termed ‘Hauser’ bases 3

(Scheme 1B),⁷and their LiCl complexes, known as ‘Knochel-Hauser’ or ‘turbo-Hauser’ bases

4, are governed by similar principles.^8,9These reagents have been mostly used in the selective

magnesiation of C–H bonds.¹⁰They are structurally diverse and the amide ligand can occupy

bridging or terminal positions.^8,9,11-13Hauser bases have been combined with Grignard reagents

to drive the most challenging deprotonations. The resulting organomagnesium amides (5; R–

Mg–NR₂) turn the acid-base reaction irreversible through deprotonation of the initially formed

amine with the magnesium alkyl.¹⁴The solution dynamics of these reagents are significantly

more complex than their parent components. The Schlenk (diorganomagnesium and

magnesium halide clusters) and aggregation (monomeric, dimeric, etc.) equilibria on the

Grignard and Hauser base co-exist with various heteroleptic organomagnesium amide

complexes. Understandably, the structural information on these systems is limited to solid-state

studies, in which dimeric structures with bridging amide ligands are most common (see 5,

Scheme 1A).¹⁵

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A

“linear” dimer

R

LiCl complex

“ate” complex

X

R

S

X

+

S

X

Li

–

Mg

Li

0.5

R

Mg

Cl

X

Cl

S

R

S

1a

1b

1c

LiCl

S

dialkylMg

R

S

Mg

R

Mg

–0.5 MgX₂

X

MgX₂

“

X

0.5

X

R–MgX

0.5

Mg

S

R

Mg

1

R

X

S

DIPAMgCl

(see below)

DIPAMgCl•LiCl

(see below)

2

1d [ X-ray ]

homometallic

open cubane

(i-Pr)₂

R

S

N

“ RMgDIPA·MgCl₂·LiCl “

Mg

N

S

R

6

(i-Pr)₂

turbo-organoMg amide

reactive structure?

5

organoMg amide

solid-state structure

solution structure unknown

this work

(i-Pr)₂

N

B

Cl

S

N

(i-Pr)₂

2 LiCl

S

Cl

Mg

Li

Mg

Li

Mg

S

N

(i-Pr)₂

Cl

3a

(i-Pr)

N

S

2

4a

[( -DIPA)MgCl·LiCl]₂

[ solution ]

[( -DIPA)MgCl]₂

[ solution ]

(i-Pr)₂

N

Cl

N

(i-Pr)₂

S

Cl

Mg

Li

2

N

(i-Pr)₂

Cl

S

Cl

S

ꢀꢁꢂ

[( -DIPA)MgCl]₂

[ solid-state ]

ꢃꢁꢂ

[( -DIPA)MgCl·LiCl]

[ solution ]

Scheme 1. Relevant structures involved in the solution equilibria of Grignard reagents and

their organomagnesium amides (A), or Hauser and Knochel-Hauser bases (B). For simplicity,

only the most common dominant species are shown. DIPA, diisopropylamide; S, solvent.

Recently, Mendoza and co-workers discovered the differential reactivity of Grignard

reagents 1 upon the addition of a specific Knochel-Hauser base (DIPAMgCl·LiCl; 4a) in the

context of Pummerer-type reactions (Scheme 2A).¹⁶This process allows the direct

transformation of sulfoxides 7 into a-functionalized sulfides 8. Unlike conventional

electrophilic Pummerer reactions, this method is compatible with strong and localized alkyl-,

aryl-, vinyl- and alkynyl-Grignard nucleophiles. This work introduced the potential of turbo-

magnesium amides as activators of organometallics, beyond their role as bases in earlier

work.^10,14Surprisingly, the mixture of Grignard 1 and DIPAMgCl·LiCl (4a) eluded the fast S-

Mg exchange that occurs between Grignards 1 and sulfoxides 7 at cryogenic temperatures.¹⁷

Interestingly, control experiments without 4a (entries 1 and 2; Scheme 2A) or with a similar

Knochel-Hauser base 4b (entry 3) clearly indicated the importance of the diisopropylamide

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fragment,⁸which pointed to a critical aggregation of Grignard 1 with the base 4a into a new

turbo-organomagnesium amide species 6. It was also found that LiCl (entry 4), and in particular

the 1:1:1 stoichiometry between the Grignard, the base and LiCl, are critical for the success of

this reaction (entries 5 and 6). Moreover, it was recently found that the same Grignard-

DIPAMgCl·LiCl combination is uniquely more reactive and more selective in addition

reactions to challenging carboxylate anions.¹⁸This further suggests that a new species is

formed in solution upon mixing Grignard reagents 1 and DIPAMgCl·LiCl (4a), and this is

relevant for the new reactivity observed.

A

#

deviation

8 (%)

R–MgX

+

DIPAMgCl·LiCl

1

2

3

4

5

6

94

10

14

41

61

53

–

S

O

S

w/o DIPAMgCl·LiCl

TMPMgCl·LiCl (4b)

DIPAMgCl (3a)

extra LiCl (1 equiv.)

extra LiCl (2 equiv.)

ꢀꢁ

R

ꢀꢁ

Me

THF, r.t.

7

8

B

-oxide

elimination

“ RMgDIPA·MgCl₂·LiCl “

(6)

O

S

O

S

[Mg]

ꢀꢁ

“ – [MgXO]^{– “}

ꢀꢁ

Me

– DIPA-H

7

9

sulfoxide anion

“ R–MgX “ (1) or

“ RMgDIPA·MgCl₂·LiCl “

(6)

- simplified mechanism

- role of LiCl?

- aggregation state?

- no S-Mg exchange

S

ꢀꢁ

“ – [MgX]^{+ “}

R

8

10

nucleophilic

addition

sulfonium

intermediate

Scheme 2. (A) Pummerer coupling between sulfoxides and Grignard reagents 1 mediated by

the turbo-Hauser base DIPAMgCl·LiCl (4a) including key optimization studies.¹⁶(B) Previous

mechanistic proposal.

Although the exact mechanism of the Grignard activation by DIPAMgCl·LiCl (4a) in this

process was unclear, the initially proposed mechanism was consistent with previous knowledge

on related b-functionalized organolithiums¹⁹and Pummerer reactions (Scheme 2B).²⁰The

deprotonation of the sulfoxide 7 would produce a sulfoxide anion 9, which would undergo S–

O bond excision through b-oxide elimination¹⁹to generate a Pummerer sulfonium intermediate

10.²⁰The latter would react with an undefined nucleophilic Grignard species 1,6 to generate

the thioether product 8.

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To gain insight into the intimate mechanism of activation of the Grignard reagent 1

bestowed by the Knochel-Hauser base 4a, we set out to undertake a computational and kinetic

profiling of this system. At the onset, it is important to underscore that only solid-state

information existed on some organomagnesium amides 5¹⁵and none on the LiCl adducts 6 that

seemed to be responsible for the differential reactivity observed (see Scheme 2A). Given the

complex equilibria that may be at place in solutions of turbo-organomagnesium amides 6, the

combined experimental-computational approach allows to evaluate the energies of various

aggregates, as well as their relative relevance for the reactivity towards sulfoxides 7.

Results and Discussion

In both the experimental and computational investigations described below, the reaction

was studied using methyl phenyl sulfoxide (7a) and isopropylmagnesium chloride (1e) as

representative reactants.

1

First, we set out to observe the evolution of the system using in situ no-D H-NMR

spectroscopy. The sulfoxide 7a displayed broadened and shifted resonances when the base

DIPAMgCl·LiCl 4a and Grignard 1e were subsequently added, thus suggesting interaction

through several complexes in equilibrium (see SI). This mixture is unstable and evolves into

the product even at low temperature, thus preventing structural studies on this equilibrium by

NMR or XRD. As discussed above, the dominant structures participating in this rapid

equilibrium may not be relevant for the reactivity, and the reactive species may be minor

components. The formation of the product could be monitored by NMR, finding that the

reaction reached 91% yield in about 3h at 25°C (Scheme 3).

Next, we employed density functional theory (DFT) calculations, in the form of the

dispersion-corrected B3LYP method,^21,22to determine the structures of the most stable species

that can form initially under the experimental conditions. To that end, we optimized the

structures of various aggregates that can form prior to the addition of the sulfoxide, and

compared their energies to those of the monomer of the magnesium amide and the dimer of the

Grignard reagent, as these two have been reported to be dominant forms of the respective

reagents in solution.^8,4bThis study concluded that the aggregation of the Grignard reagent and

DIPAMgCl·LiCl results in more stable heteroleptic aggregates (see SI for details).

The two most stable complexes with linear topology and two open cubane complexes were

then used to explore the coordination of the sulfoxide substrate. In all cases, the exchange of

one solvent molecule for the sulfoxide at the terminal magnesium resulted in complexes that

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are 3-6 kcal/mol more stable (see SI). The exothermic character of this ligand substitution is

consistent with the interaction observed by ¹H-NMR in the reaction mixture (see above). The

resulting complexes A-D are shown in Figure 1 along with their calculated relative energies.

Complex A consists of two magnesium ions bridged by the amide and a chloride ion. One

magnesium ion binds the sulfoxide and the isopropyl moiety, while the other ion binds a second

chloride and a THF molecule. Complex B is essentially the lithium chloride adduct of complex

A, where two chlorides bridge the Mg and the Li ions. This structural motif is commonly found

in related Grignard and Hauser-base complexes.^8-10,12The energy of complex B is only 0.2

kcal/mol higher than complex A.

Despite not being reported in structural studies, we explored the feasibility of the

magnesium-lithium heterometallic open cubanes C and D as reactive intermediates. Similar

cubane and open cubane structures have been implicated in unrelated reactions involving

potassium²³or zinc aggregates.²⁴Complex C features two magnesium ions linked by the amide

and a chloride, with additional chloride bridges with the lithium ion to complete the compact

structure. This species is calculated to be +3.3 kcal/mol relative to complex A. Complex D is

a dimer formed of two units of complex C. This aggregate is calculated to be only 4.4 kcal/mol

higher than complex A. As seen in Figure 1, in complexes A-D the amide bridges two

magnesium ions while the sulfoxide and alkyl ligand bind to a single magnesium. Exchanging

of the positions of the amide and sulfoxide leads to higher energies (see SI).

–

Me

Ph

+

O

S

THF

(i-Pr)₂

N

Ph

+

–

Mg

Cl

Ph

+

–

Li

(i-Pr)₂

THF

(i-Pr)₂

Cl

S

O

Cl

S

O

Mg i-Pr

N

Ph

N

THF

Cl

Me

Li

Cl

Me

Mg

Li

S

Mg

Me

Li

Mg

+

Cl

O

Cl

i-Pr

Cl

Mg

(i-Pr)₂

i-Pr Mg

Cl

i-Pr

N

(i-Pr)₂

–

Cl

Ph

+

S

N

–

O

Me

A (0.0)

B (+0.2)

C (+3.3)

D (+4.4)

Cl

Li

Mg

Figure 1. Structures of the four starting complexes used to study the reaction mechanism.

Relative energies are indicated in kcal/mol. For important distances in these structures, see SI.

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Next, we calculated the full reaction mechanisms starting from these four complexes. The

calculations show that they follow essentially the same reaction mechanism, consisting of the

following steps: 1) a ligand rearrangement into a µ-sulfoxide / s-amide disposition, 2) a proton

transfer from the sulfoxide a-carbon to the amide, forming a sulfoxide enolate featuring an

S=C double bond, and finally 3) a nucleophilic addition of the isopropyl moiety to the sp²

carbon of the sulfoxide anion taking place concertedly with the cleavage of the S–O bond. The

latter of these steps is a surprising anion-anion C–C coupling that contrasts with electrophilic

Pummerer reactions via sulfonium intermediates 10.²⁰

As shown in Figure 2, the calculations demonstrate that the two linear complexes A and B

have very similar reaction energy profiles. The optimized geometries of the intermediates and

transition states (TSs) for both complexes are given in the SI. The last step was found to be

rate-determining for both cases, with a calculated barrier of 27.1 kcal/mol for complex A and

28.1 kcal/mol for complex B. An important observation here is that, in contrast to previous

proposals,^16athe b-oxide elimination pathway¹⁹to form a discrete sulfonium intermediate²⁰

could not be obtained by the calculations (see SI for details).

The overall barriers calculated for these two complexes are not compatible with the reaction

time and temperature used in the experiments, indicating that the two considered linear

complexes might not be the active species in the reaction. Furthermore, the fact that identical

mechanisms were obtained for complexes A and B, with very similar barriers, suggests that

other linear complexes (e.g. complexes E-K in the Supporting Information) are also likely to

behave similarly, yielding high barriers. These complexes were therefore not considered

further by the calculations.

Figure 2. Free-energy profile of the reaction mechanism of complexes A and B. Relative

energies are in kcal/mol.

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We then turned our attention to reactions starting from the open cubane structures C and D.

These two complexes gave similar energy profiles compared to each other, but very different

compared to the linear structures discussed above. The calculated energy graph and the

optimized geometries of the intermediates and transition states for the reaction starting from

complex C are depicted in Figures 3 and 4, while the corresponding figures for complex D are

given in the SI.

According to this mechanism, the first step also here is the formation of the intermediate

with the sulfoxide in the bridging position and the amide in the terminal one (σ-amide; Int1-

C). The energy of this intermediate is 7.7 kcal/mol higher than complex C, i.e. +11.0 kcal/mol

compared to the most stable complex A. This rearrangement is necessary, as the direct

deprotonation of the sulfoxide in the terminal position is associated with high barriers (see SI),

probably due to the coordinative saturation of the bridged amide (μ-amide) that prevents the

proton abstraction. Next, Int1-C undergoes a second rearrangement step to form Int2-C, 2.2

kcal/mol higher in energy, in which the oxygen of the sulfoxide is bound to the three metallic

ions (see Figures 3 and 4). Int2-C can then undergo the intramolecular proton transfer through

TS1-C, which has an accumulated barrier of 16.8 kcal/mol relative to complex C, i.e. 20.1

kcal/mol relative to the most stable species, complex A. Interestingly, in the resulting Int3-C

(Figure 4), the anionic carbon of the sulfoxide enolate binds to the Mg ion (Mg–C distance

2.22 Å), displacing the oxygen, which is no longer bridging (Mg–O distance 2.66 Å). At Int2-

C, the alternative proton transfer to the isopropyl moiety has a more than 11 kcal/mol higher

barrier compared to TS1-C and can be ruled out (see SI).

Figure 3. Free-energy profile of the reaction mechanism of complex C. Relative energies are

in kcal/mol.

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Int3-C is calculated to be 14.1 kcal/mol lower than Int2-C (-0.9 kcal/mol relative to

complex A), and in order for the reaction to proceed, another rearrangement step is necessary,

namely the sulfoxide rotates around the S–O bond to form Int4-C, which is calculated to be

5.5 kcal/mol higher than Int3-C. This rotation breaks the Mg–C coordination, resulting in an

sp²-hybridized anion in close proximity with the isopropyl moiety (Int4-C). In the final step

of the reaction, the isopropyl adds to the sulfoxide enolate concertedly with the cleavage of the

S–O bond to form the final product, similarly to the mechanism found for the linear complexes

A and B. The cumulative barrier for this step is calculated to be 15.2 kcal/mol relative to Int3-

C (see Figure 3). In the transition state for the C–C bond formation (TS2-C), the Li–O distance

is 1.82 Å, which is 0.17 Å shorter than in the preceding intermediate due to the increasing

negative charge on the oxygen. This shorter distance, in turn, increases the congestion in the

complex, which results in the chloride that is bridging the Li and Mg ions becoming terminal.

The rate-determining barrier of this mechanism is thus 20.1 kcal/mol, which is 7-8 kcal/mol

lower than the barriers obtained for the linear complexes A and B. Interestingly, the energies

for the reaction starting from the double cubane complex D are similar to those of complex C

(details given in SI), with a calculated rate-determining barrier of 24.9 kcal/mol. Hence, despite

the fact that the cubane starting structures are slightly higher in energy compared to the linear

ones (Figure 1), they lead to reaction mechanisms with lower barriers. One reason is the greater

extent of electrostatic stabilization of the negative charge of the oxygen upon cleavage of the

S–O bond due to the complexation of the lithium ion. This stabilization can be detected from

the shortening of the Li–O distance at the last step, and also from the much lower energy of the

final product, which is calculated to be much more stable than the products of the linear

complexes (compare, for example, Prod-C in Figure 3 with Prod-A in Figure 2).

It is also interesting to note that the S–O bond distance of the sulfoxide enolate of Int4-C

is 0.10 Å longer than the corresponding distance for complex B. Moreover, the sp²carbon in

Int4-C has less negative charge (–0.82) compared to the corresponding intermediate for

complex B (–0.97), indicating that the carbon in Int4-C would facilitate coupling with the alkyl

nucleophile in the case of the open cubane structure (see SI for details).

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Li

Cl

Mg

Int1-C

Int2-C

1.40

2.66

1.60

2.22

1.35

TS1-C

Int3-C

1.82

1.99

2.23

2.87

2.33

1.64

1.98

1.82

1.63

Int4-C

TS2-C

Figure 4. Optimized geometries of the intermediates and transition states of the reaction

mechanism for complex C. Selected distances are given in Angstrom.

An important difference between the reactions of the linear complexes and the cubane ones

is that the C–C bond formation is rate-limiting in the former, while in the latter the proton

transfer step is rate-limiting. The fact that this step is also irreversible implies that one would

expect to observe a primary kinetic isotope effect (KIE) when using an analogous deuterated

substrate if the predictions of the calculations are correct. Indeed, we observed a significantly

slower reaction using sulfoxide 7a-d₃, reaching only 48% yield in the first 3.3 hours as

evidenced by ¹H-NMR (Scheme 3). This contrasts with the complete conversion in the same

time obtained with the protonated substrate 7a. However, the complex kinetics observed in the

system prevented an accurate determination of the KIE value. The deprotonation equilibrium

could also affect the KIE observed, but the irreversible deprotonation predicted by the

calculations makes this scenario less likely. The mechanism involving chiral cubane

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intermediates presented herein may also explain the partial chirality transfer observed for more

complex substrates,^16awhich was initially ascribed to an intimate sulfonium ion pair in line

with earlier Pummerer literature.

H

0.1

S

O

S

1e · 4a

Ph

H

D

i-Pr

8a

Ph

CH₃

THF, r.t.

7a

[8]

(M)

8a

D

8a-d₂

O

S

1e · 4a

0

Ph

CD₃

i-Pr

8a-d₂

THF, r.t.

0

1

2

3

4

5

6

7

7a-d₃

t (h)

Scheme 3. The slower reaction with a deuterated substrate 7a-d₃is consistent with the rate-

determining deprotonation predicted by the calculations.

Conclusions

In summary, the Pummerer reaction between sulfoxides and Grignard nucleophiles

activated by turbo-Hauser bases has been calculated to occur through an open-cubane

heterometallic turbo-organomagnesium amide. The caged topology of this intermediate is

crucial to facilitate the activation of the S–O bond and stabilize the negative charge on the

sulfoxide enolate carbon. Surprisingly, the formation of the new C–C bond occurs through a

concerted anion-anion coupling with concomitant cleavage of the S–O bond. This contrasts

with conventional Pummerer-type reactions operating through electrophilic intermediates.

These insights explain the critical role of LiCl in nucleophilic Pummerer coupling, and open

new avenues for research in new synthetic methods based on the synergy between Knochel-

Hauser bases and Grignard reagents.

Computational Methods

All the calculations were performed with the package Gaussian 09²⁵and the B3LYP-D3(BJ)

functional.^21,22Geometry optimizations and frequency calculations were carried out with the

6-31G(d,p) basis set. Solvation effects were considered by performing single-point calculations

with the SMD model and THF as solvent.²⁶To obtain better accuracy, the electronic energies

of the optimized structures were calculated using single-point calculations with the larger basis

set 6-311+G(2d,2p). Vibrational frequencies were calculated at the same level of theory as the

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geometry optimization, and the Gibbs free energy corrections were calculated using the rigid-

rotor-harmonic-oscillator (RRHO) approximation at room temperature. Standard state

corrections to account for the conversion from the 1 atm ideal gas to the 1 M standard state for

the solutes and the 12.3 M for the solvent were included. This correction was done by adding

the term RT ln(24.5) = +1.9 kcal/mol for the solutes and RT ln(24.5·12.3) = +3.4 kcal/mol for

the solvent.

Supporting Information

Further computational results, absolute energies and energy corrections, and Cartesian

coordinates of reported structures (PDF). Experimental procedures, kinetic monitoring and

data analysis (PDF).

Acknowledgements

FH thanks the Swedish Research Council for financial support. AM thanks the Knut and Alice

Wallenberg Foundation (KAW2016.0153) and the European Research Council (714737) for

financial support.

References

1. (a) Knochel, P. In Organometallics in Synthesis: Organomagnesium and Organozinc

Chemistry: Wiley, VCH; 2013. (b) Knochel, P.; Kmsovskiy, A.; Sapountzis, L. In Handbook

of Functionalized Organometallics: Applications in Synthesis. Weinheim: Wiley-VCH; 2008

(c) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis,

I.; Vu, V. A. Highly Functionalized Organomagnesium Reagents Prepared through Halogen-

Metal Exchange. Angew. Chem., Int. Ed. 2003, 42, 4302–4320.; For an account on the use of

Grignard reagents in process scale, see: (d) Tilstam, U.; Weinmann, H. Activation of Mg Metal

for Safe Formation of Grignard Reagents on Plant Scale. Org. Proc. Res. Dev. 2002, 6, 906–

910.

2. (a) For an NMR solution study on Grignard and turbo-Grignard reagents, see:

Schnegelsberg, C.; Bachmann, S.; Kolter, M.; Auth, T.; John, M.; Stalke, D.; Koszinowski, K.

Association and Dissociation of Grignard Reagents RMgCl and Their Turbo Variant

RMgCl⋅LiCl. Chem. - Eur. J. 2016, 22, 7752–7762.; (b) For an X-ray and CSI-MS study on

Grignard reagents, see: Sakamoto, S.; Imamoto, T.; Yamaguchi, K. Constitution of Grignard

12

10.1002/chem.202004164

Chemistry - A European Journal

Reagent RMgCl in Tetrahydrofuran. Org. Lett. 2001, 3, 1793–1795.

3. Peltzer, R. M.; Gauss, J.; Eisenstein, O.; Cascella, M. The Grignard Reaction – Unraveling

a Chemical Puzzle. J. Am. Chem. Soc. 2020, 142, 2984-2994.

4. (a) Seyferth, D. The Grignard Reagents. Organometallics. 2009, 28, 1598–1605.; (b) For a

recent computational study, see: Peltzer, R. M.; Eisenstein, O.; Nova, A.; Cascella, M. How

Solvent Dynamics Controls the Schlenk Equilibrium of Grignard Reagents: A Computational

Study of CH₃MgCl in Tetrahydrofuran. J. Phys. Chem. B. 2017, 121, 4226-4237.

5. For a comprehensive structural review, see: Harrison-Marchand, A.; Mongin, F. Mixed

AggregAte (MAA): A Single Concept for All Dipolar Organometallic Aggregates. 1.

Structural Data. Chem. Rev. 2013, 113, 7470-7562.

6. (a) Krasovskiy, A.; Knochel, P., A LiCl-Mediated Br/Mg Exchange Reaction for the

Preparation of Functionalized Aryl- and Heteroarylmagnesium Compounds from Organic

Bromides. Angew. Chem., Int. Ed. 2004, 43, 3333-3336.; (b) Knochel, P.; M. Barl, N.; Werner,

V.; Sämann, C., The Halogen/Magnesium-Exchange Using i-PrMgCl·LiCl and Related

Exchange Reagents. Heterocycles. 2014, 88, 827-844.

7. (a) Hauser, C. R.; Walker, H. G. Condensation of Certain Esters by Means of

Diethylaminomagnesium Bromide. J. Am. Chem. Soc. 1947, 69, 295–297; Eaton introduced

DIPA and TMP as hindered magnesium bases: (b) Eaton, P. E.; Lee, C. H.; Xiong, Y.

Magnesium Amide Bases and Amido-Grignards. 1. Ortho Magnesiation. J. Am. Chem. Soc.

1989, 111, 8016–8018.

8. Neufeld, R.; Teuteberg, T. L.; Herbst-Irmer, R.; Mata, R. A.; Stalke, D. Solution Structures

of Hauser Base ⁱPr₂NMgCl and Turbo-Hauser Base ⁱPr₂NMgCl·LiCl in THF and the Influence

of LiCl on the Schlenk-Equilibrium. J. Am. Chem. Soc. 2016, 138, 4796–4806.; (b) Neufeld,

R.; Stalke, D., Solution Structure of Turbo-Hauser Base TMPMgCl⋅LiCl in [D8]THF. Chem.

Eur. J. 2016, 22, 12624-12628; (c) Armstrong, D. R.; García-Álvarez, P.; Kennedy, A. R.;

Mulvey, R. E.; Parkinson, J. A. Diisopropylamide and TMP Turbo-Grignard Reagents: A

Structural Rationale for their Contrasting Reactivities. Angew. Chem., Int. Ed. 2010, 49,

3185−3188.

9. For the solid-state structure of TMPMgCl·LiCl, see: (a) García-Álvarez, P.; Graham, D. V.;

Hevia, E.; Kennedy, A. R.; Klett, J.; Mulvey, R. E.; O’Hara, C. T.; Weatherstone, S.

Unmasking Representative Structures of TMP-Active Hauser and Turbo-Hauser Bases.

Angew. Chem., Int. Ed. 2008, 47, 8079–8081.; For the solid-state structure of DIPAMgCl·LiCl,

see ref. 8c.

13

10.1002/chem.202004164

Chemistry - A European Journal

10. (a) Melzig, L.; Rauhut, C. B.; Knochel, P. 2,3-Functionalization of Furans, Benzofurans

and Thiophenes via Magnesiation and Sulfoxide-Magnesium Exchange. Chem. Commun.

2009, 24, 3536–3538.; (b) Rohbogner, C. J.; Wunderlich, S. H.; Clososki, G. C.; Knochel, P.

New Mixed Li/Mg and Li/Mg/Zn Amides for the Chemoselective Metallation of Arenes and

Heteroarenes. Eur. J. Org. Chem. 2009, 11, 1781–1795.; (c) Clososki, G. C.; Rohbogner, C.

J.; Knochel, P. Direct Magnesiation of Polyfunctionalized Arenes and Heteroarenes Using

(Tmp)₂Mg⋅2ꢀLiCl. Angew. Chem., Int. Ed. 2007, 46, 7681–7684.; (d) Krasovskiy, A.;

Krasovskaya, V.; Knochel, P. Mixed Mg/Li Amides of the Type R₂NMgCl⋅LiCl as Highly

Efficient Bases for the Regioselective Generation of Functionalized Aryl and Heteroaryl

Magnesium Compounds. Angew. Chem., Int. Ed. 2006, 45, 2958–2961.

11. Hauser-bases like DIPAMgCl are mostly dimeric species that display bridging amido

ligands in the solid-state. However, they have been shown to be likely chloro-bridged in

solution, thus illustrating the small energetic difference between these coordination manifolds

(see ref. 8)

12. The Knochel-Hauser bases DIPAMgCl.LiCl is dimeric in the solid state with bridging

amide ligands, but equilibrates with its monomer in solution (see ref. 8).

13. For Hauser bases with terminal bulky amide ligands, see: (a) [HMDSMgBr]₂:Yang, K. C.;

Chang, C. C.; Huang, J. Y.; Lin, C. C.; Lee, G. H.; Wang, Y.; Chiang, M. Y. Synthesis,

Characterization and Crystal Structures of Alkyl-,Alkynyl-,Alkoxo- and Halo-Magnesium

Amides. J. Organometalic. Chem. 2002, 648, 176–187.; (b) [HMDSMgCl]₂: Bartlett, R. A.;

Olmstead, M. M.; Power, P. P. Structural Characterization of the “Magnesylamine”

[(Et₂O)Mg(Cl){N(SiMe₃)₂}]₂

and

the

Two-Coordinate

Magnesium

Amide

Mg{N(SiMePh₂)₂}₂. Inorg. Chem. 1994, 33, 4800–4803.; (d) [(Bn₂N)₂Mg]₂.2THF: Clegg, W.;

Craig, F. J.; Henderson, K. W.; Kennedy, A. R.; Mulvey, R. E.; O’Neil, P. A.; Reed, D. Solid

State Structures and Dynamic Solution Equilibria of Bis(Dibenzylamido)Magnesium

Complexes: Aggregation Dependence on Stoichiometry and Denticity of Donor Solvent.

Inorg. Chem. 1997, 36, 6238–6246.; (e) For monomeric (HMDS)₂Mg.2THF, see: Bradley, D.

C.; Hursthouse, M. B.; Ibrahim, A. A.; Malik, K. M. A.; Motevalli, M.; Moseler, R.; Powell,

H.; Runnacles, J. D.; Sullivan, A. C. Synthesis and chemistry of the bis (trimethylsilyl) amido

bis-tetrahydrofuranates of the group 2 metals magnesium, calcium, strontium and barium. X-

ray crystal structures of Mg[N(SiMe₃)₂]₂·2THF and related Mn[N(SiMe₃)₂]₂·2THF.

Polyhedron, 1990, 9, 2959–2964.

14. Organomagnesium amides are structurally characterized bases for challenging metallation

14

10.1002/chem.202004164

Chemistry - A European Journal

reactions: (a) Zhang, M.-X.; Eaton, P. E., BuMgNⁱPr₂: A New Base for Stoichiometric,

Position-Selective Deprotonation of Cyclopropane Carboxamides and Other Weak CH Acids.

Angew. Chem., Int. Ed. 2002, 41, 2169–2171.; (b) Conway, B.; Hevia, E.; Kennedy, A. R.;

Mulvey, R. E.; Weatherstone, S., Synthesis and Characterisation of a Series of

Alkylmagnesium Amide and Related Oxygen-Contaminated "Alkoxy" Compounds. Dalton

Trans. 2005, 1532–1544.; (c) Rappoport, Z.; Marek, I. The Chemistry of Organomagnesium

Compounds; John Wiley & Sons Ltd., 2008.

15. For X-ray structures of organomagnesium amides, see: (a) i-PrMg(DIPA) and EtMg(TMP):

Coates, G. E.; Ridley, D. Some Amino-Alkylmagnesium Complexes: Evidence for Three-Co-

Ordinate Magnesium. J. Chem. Soc. A. Inorganic, Phys. Theor. Chem. 1967, 56–59. (b) s-

BuMg(HMDS) and t-BuMg(NR₂) - NR₂= DIPA, HMDS, TMP, Cy₂N, Bn₂N: see ref. 14b.; (c)

n-BuMg(TMP): Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; Weatherstone, S. Synthesis and

Crystal Structure of [{ⁿBuMg(μ-TMP)}₂] and of a Homometallic Inverse Crown in

Tetranuclear [{ⁿBuMg₂[μ-N(H)Dipp]₂(μ³-OnBu)}₂]. Angew. Chem., Int. Ed. 2004, 43, 1709–

1712.; (d) RCCMg(DIPA) - R= Ph, TMS: see ref. 13a.; (e) t-BuMg(NHt-Bu): Olmstead, M.

M.; Grigsby, W. J.; Chacon, D. R.; Hascall, T.; Power, P. P. Reactions between Primary

Amines and Magnesium or Zinc Dialkyls: Intermediates in Metal Imide Formation. Inorganica

Chim. Acta 1996, 251, 273–284.; (f) MeMg(NHTIPS): Westerhausen, M.; Bollwein, T.;

Makropoulos, N.; Piotrowski, H. Ligand Exchange Reaction between an Alkylzinc Primary

Amide and a Dialkylmagnesium Compound: Crystal Structures of [(THF)MeMg-μ-

N(H)Si(ⁱPr) ₃]₂and (TMEDA)Mg[N(H)Si(i-Pr)₃]₂. Inorg. Chem. 2005, 44, 6439–6444.; (g) For

a chelate organomagnesium amide: Henderson, K. W.; Mulvey, R. E.; Dorigo, A. E. Solvent

induced disproportionation of alkyl(amido)magnesium species containing a (2-pyridyl)amido

unit: synthetic, theoretical and NMR spectroscopic studies of bis(amido)magnesium

compounds. J. Organomet. Chem. 1996, 518, 139–146.; (h) For a review, see: Pinkus, A. G.

Three-coordinate Magnesium: Coord. Chem. Rev. 1978, 25, 173–197.

16. (a) Colas, K.; Martin-Montero, R.; Mendoza, A. Intermolecular Pummerer Coupling with

Carbon Nucleophiles in Non-Electrophilic Media. Angew. Chem., Int. Ed. 2017, 56, 16042–

16046.; (b) Colas, K.; Mendoza, A. Iterative Synthesis of Pluripotent Thioethers through

Controlled Redox Fluctuation of Sulfur. Synlett 2018, 29, 1329–1333.

17. (a) Ruppenthal, S.; Brückner, R. Symmetric Diarylsulfoxides as Asymmetric Sulfinylating

Reagents for Dialkylmagnesium Compounds. J. Org. Chem. 2015, 80, 897–910.; (b) Li-Yuan

Bao, R.; Zhao, R.; Shi, L. Progress and Developments in the Turbo Grignard Reagent i-

PrMgCl·LiCl: A Ten-Year Journey. Chem. Commun. 2015, 51, 6884–6900.; (c) Rauhut, C. B.;

15

10.1002/chem.202004164

Chemistry - A European Journal

Melzig, L.; Knochel, P. Meta- and Para-Difunctionalization of Arenes via a Sulfoxide-

Magnesium Exchange Reaction. Org. Lett. 2008, 10, 3891–3894.; (d) Shi, L.; Chu, Y.;

Knochel, P.; Mayr, H. Leaving Group Dependence of the Rates of Halogen-Magnesium

Exchange Reactions. Org. Lett. 2012, 14, 2602–2605.; (e) Casoni, G.; Kucukdisli, M.;

Fordham, J. M.; Burns, M.; Myers, E. L.; Aggarwal, V. K. α-Sulfinyl Benzoates as Precursors

to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters. J.

Am. Chem. Soc. 2017, 139, 11877–11886.; (f) Oae, S.; Uchida, Y. Ligand-Coupling Reactions

of Hypervalent Species. Acc. Chem. Res. 1991, 24, 202–208.

18. Colas, K.; dos Santos, A. Catarina V. D.; Mendoza, A. i-Pr₂NMgCl·LiCl Enables the

Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions. Org.

Lett. 2019, 21, 7908–7913.

19. For seminal work, see: (a) Eisch, J. J.; Galle, J. E. Organosilicon compounds with

functional groups proximate to silicon. Feasible route to 1,2-epoxyalkyllithium reagents via

the lithiation of epoxyethylsilanes. J. Am. Chem. Soc. 1976, 98, 4646-4648; for applications of

b-oxyfunctionalized organolithiums, see: (b) Barluenga, J.; Yus, M.; Concellon, J. M.; Bernad,

P. Direct and regioselective transformation of a-chlorocarbonyl compounds into alkenes and

deuteroalkenes. J. Org. Chem. 1981, 46, 2721-2726.; (c) Barluenga, J.; Yus, M.; Concellón, J.

M.; Bernad, P. One-pot and regioselective synthesis of alkenes and deuterioalkenes from α-

chlorocarboxylic acid chlorides via a tandem addition of two different nucleophiles (Grignard

reagents, hydride or deuteride) and further lithiation. J. Org. Chem. 1983, 48, 609-611.; (d)

Barluenga, J.; Yus, M.; Concellón, J. M.; Bernad, P. Direct one-pot synthesis of terminal

olefins and deuterio olefins from carboxylic acid chlorides. J. Org. Chem. 1983, 48, 3116-

3118.; for a comprehensive review, see: (e) Nájera, C.; Yus, M. Functionalized Organolithium

Compounds: New Synthetic Adventures. Curr. Org. Chem. 2003, 7, 867-926.

20. (a) García Ruano, J. L.; Alemán, J.; Cid, M. B.; Fernández-Ibáñez, M. Á.; Maestro, M. C.;

Martín, M. R.; Martín-Castro, A. M. In Organosulfur Chemistry in Asymmetric Synthesis:

Asymmetric Transformations Mediated by Sulfinyl Groups: Wiley-VCH; Weinheim, 2009. (b)

Bur, S. K. In Comprehensive Organic Synthesis: Polonovski- and Pummerer-Type Reactions

and the Nef Reaction: Elsevier Ltd., 2014. (c) Feldman, K. S. Modern Pummerer-Type

Reactions. Tetrahedron. 2006, 62, 5003–5034. (d) Pulis, A. P.; Procter, D. J. C−H Coupling

Reactions Directed by Sulfoxides: Teaching an Old Functional Group New Tricks. Angew.

Chem., Int. Ed. 2016, 55, 9842–9860. (e) Bur, S. K.; Padwa, A. The Pummerer Reaction:

Methodology and Strategy for the Synthesis of Heterocyclic Compounds. Chem. Rev. 2004,

16

10.1002/chem.202004164

Chemistry - A European Journal

104, 2401–2432; for selected recent examples of Pummerer-based reactions, see: (f) Kaldre,

D.; Maryasin, B.; Kaiser, D.; Gajsek, O.; González, L.; Maulide, N. An Asymmetric Redox

Arylation: Chirality Transfer from Sulfur to Carbon through a Sulfonium [3,3]-Sigmatropic

Rearrangement. Angew. Chem., Int. Ed. 2017, 56, 2212–2215; (g) Kaiser, D.; Veiros, L. F.;

Maulide, N. Brønsted Acid-Mediated Hydrative Arylation of Unactivated Alkynes. Chem. Eur.

J. 2016, 22, 4727–4732.; (h) Fernández-Salas, J. A.; Eberhart, A. J.; Procter, D. J. Metal-Free

CH-CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide

Group. J. Am. Chem. Soc. 2016, 138, 790–793; (i) Peng, B.; Huang, X.; Xie, L.-G.; Maulide,

N. A Brønsted Acid Catalyzed Redox Arylation. Angew. Chem., Int. Ed. 2014, 53, 8718–8721;

(j) Eberhart, A. J.; Procter, D. J. Nucleophilic Ortho -Propargylation of Aryl Sulfoxides: An

Interrupted Pummerer/Allenyl Thio-Claisen Rearrangement Sequence. Angew. Chem., Int. Ed.

2013, 52, 4008–4011; (k) Eberhart, A. J.; Imbriglio, J. E.; Procter, D. J. Nucleophilic Ortho

Allylation of Aryl and Heteroaryl Sulfoxides. Org. Lett. 2011, 13, 5882–5885. (l) Yorimitsu,

H. Cascades of Interrupted Pummerer Reaction-Sigmatropic Rearrangement. Chem. Rec. 2017,

17, 1156–1167. (m) Smith, L. H. S.; Coote, S. C.; Sneddon, H. E.; Procter, D. J. Beyond the

Pummerer Reaction: Recent Developments in Thionium Ion Chemistry. Angew. Chem., Int.

Ed, 2010, 49, 5832–5844.

21. Becke, A. D. Density functional Thermochemistry. III. The Role of Exact Exchange. J.

Chem. Phys. 1993, 98, 5648−5652. (b) Lee, C.; Yang, W.; Parr, R. G. Development of the

Colle-Salvetti Correlation-energy Formula into a Functional of the Electron Density. Phys.

Rev. B 1988, 37, 785−789.

22. (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate Ab Initio

parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-

Pu. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the

damping function in dispersion corrected density functional theory. J. Comput. Chem. 2011,

32, 1456–1465.

23. Liu, W.-B.; Schuman, D. P.; Yang, Y.-F.; Toutov, A. A.; Liang, Y.; Klare, H. F. T.; Nesnas,

N.; Oestreich, M.; Blackmond, D. G.; Virgil, S. C.; et al. Potassium Tert-Butoxide-Catalyzed

Dehydrogenative C−H Silylation of Heteroaromatics: A Combined Experimental and

Computational Mechanistic Study. J. Am. Chem. Soc 2017, 139, 45.

24. (a) Ishimori, M.; Hagiwara, T.; Tsuruta, Teiji.; Kai, Y.; Yasuoka, N.; Kasai, N.; The

structure and reactivity of [Zn(OMe)₂(EtZnOMe)₆]. Bul. Chem. Soc. Jap. 1976, 49, 1165-1166.

(b) Ullrich, M.; Berger, R. J. F.; Jana, S.; Pape, T.; Fröhlich, R.; Mitzel, N. W. Organozinc

Hydroxylamides: On the Bulk-Dependent Interplay of Nuclearity, Structure and Dynamics.

17

10.1002/chem.202004164

Chemistry - A European Journal

Dalt. Trans. 2011, 40, 1144–1157. (c) Petrus, R.; Sobota, P. Zinc Complexes Supported by

Maltolato Ligands: Synthesis, Structure, Solution Behavior, and Application in Ring-Opening

Polymerization of Lactides. Organometallics. 2012, 31, 4755–4762. (d) Athavale, S. V.;

Simon, A.; Houk, K. N.; Denmark, S. E. Demystifying the Asymmetry-Amplifying,

Autocatalytic Behaviour of the Soai Reaction through Structural, Mechanistic and

Computational Studies. Nat. Chem. 2020, 12, 412–423.

25. Gaussian 09, Revision E.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,

M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H.

Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.

Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,

Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M.

Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J.

Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N.

Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.

Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,

R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S.

Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,

Gaussian, Inc., Wallingford CT, 2013.

26. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal solvation model based on solute

electron density and a continuum model of the solvent defined by the bulk dielectric constant

and atomic surface tensions. J. Phys. Chem. B. 2009, 113, 6378–6396.

18

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