Mechanochemistry inOrganic Synthesis
2019/3/28
M2 Kentaro Sakai

Today’s Topics

1. Introduction
2. Mechanochemistry in Organic Synthesis
3. Recent Example
4. Summary

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1. Introduction

What is Mechanochemistry?

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Definition (IUPAC)“a chemical reaction that is induced by the directabsorption of mechanical energy”
IUPAC Compendium of Chemical Terminology, ed. M. Nič, J.
Jirát, B. Košata, A. Jenkins and A. McNaught, IUPAC, 2009.

Image

History of Mechanochemistry

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S. L. James et al. Chem. Soc. Rev. 2012, 41, 413.
1820 (M. Faraday)
AgCl→Ag (with some metals such as Zn, Cu, Sn, Fe)1890s (C. Lea)
mechanochemical reactions could give different products
1893~1920s
cocrystalization, organic polymers
1980s~1990s
solvent-free organic reactions with additional heating
Around 2000
organic, metal-organic, supramolecular synthesis6/44

Equipment

D. L. Browne et al. Chem. Sci. 2018, 9, 3080.

✓ Ball mill is usually used for organic synthesis.

Example of Reaction Setup (Mixer Mill)

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H. Ito et al. Nat. Commun. 2019, 10, 111.

LAG (Liquid Assisted Grinding)

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W. Jones et al. Chem. Commun. 2002, 2372.

✓ Addition of MeOH enhanced the co-crystal fromation.

LAG (Liquid Assisted Grinding) (2)9/44

T. Friščić et al. CrystEngComm, 2009, 11, 418.

H. Ito et al. Chem. Eur. J. 2019, 25, 4654.

✓ LAG has been also used in organic synthesis.

Analysis Methodology in Real Time

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ex situ analysis
・FTIR (within seconds)
・powder X-ray diffraction (several minutes)
・solid-state NMR (~several hours)

In situ analysis
・synchrotron PXRD
・Raman spectroscopy
・tandem analysis (PXRD + Raman)
D. Tan, T. Friščić, Eur. J. Org. Chem. 2018, 18.

Summary of Section 1・Ball mills are usually used for mechanochemistry.

・LAG accelerates the mechanochemical reactions.
・The analysis method is limited and the reaction
mechanism is often unclear.

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2. Mechanochemistry inOrganic Synthesis

Mechanochemistry in Organic Synthesis

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Carbon-Carbon Bond-Forming Reactions
Carbon-Nitrogen Bond-Forming Reactions
Carbon-Oxygen and Other Bond-Formation Reactions
Cycloaddition Reactions
Oxidations and Reductions
・・・D. Margetić, V. Štrukil. (2016). Mechanochemical organic synthesis. Elsevier.

Some Merit of Mechanochemical Reactions

14/44✓ Solvent-free mechanochemical reactions are cleaner andsustainable.
others15%

solvent
85%

D. J. C. Constable et al. Org. Process Res. Dev. 2007, 11, 133.

✓ There are also some advantages in terms of reactivity.
1. Time saving
2. Selectivity enhancement
3. Different products from solution-based reactions

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1. Time Saving

C. Bolm et al. Chem. Eur. J. 2007, 13, 4710.

Comparison with Solution-based reaction

P. M. Pihko et al. Synlett, 2004, 1891.

2. Selectivity Enhancement

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Solution-based reaction

Mechanochemical reaction

A. M. Belenguer, T. Friščić et al. Chem. Sci. 2011, 2, 696.

3. Different Products from Solution-based Reaction

17/44✓ Different reactivity

H. Guan, J. Mack et al. ACS Sustainable Chem. Eng. 2016, 4, 2464.

✓ Solvent-sensitive products

T. P. Hanusa et al. Organometallics, 2014, 33, 5952.

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Application: Functionalization of Low Solubility Materials

K. Komatsu et al. Nature, 1997, 387, 583.

Y.-T. Su, G.-W. Wang, Org. Lett. 2013, 15, 3408.

Summary of Section 2

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・Various kinds of organic reactions are performed using aball mill.
・Improve and change the reactivity
1. Time saving
2. Selectivity enhancement
3. Different products from solution-based reactions

3. Recent Examples

Cross-Coupling Reaction

Buchwald-Hartwig Cross-Coupling in Solid-State

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H. Ito et al. Nat. Commun. 2019, 10, 111.

Screening of Ligand

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H. Ito et al. Nat. Commun. 2019, 10, 111.

Screening of LAG Additives

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H. Ito et al. Nat. Commun. 2019, 10, 111.

Transmission Electron Microscopy (TEM)

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Palladium nanoparticles in the crude reaction mixture.

✓ 1,5-cod suppressed palladium aggregations.
H. Ito et al. Nat. Commun. 2019, 10, 111.

Transmission Electron Microscopy (TEM) (2)26/44(b)with cyclooctane(c)no additives✓ Palladium was highly aggregated within 30 mins.
H. Ito et al. Nat. Commun. 2019, 10, 111.

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Kinetic Study✓ The reactions stopped after about 30 mins.
H. Ito et al. Nat. Commun. 2019, 10, 111.

Proposed Acceleration Mechanism

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without olefin

Mechanochemicalgrindingwith olefinH. Ito et al. Nat. Commun. 2019, 10, 111.

Substrate Scope (Amines)

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H. Ito et al. Nat. Commun. 2019, 10, 111.

Substrate Scope (Aryl Halides) (1)30/44

H. Ito et al. Nat. Commun. 2019, 10, 111.

Substrate Scope (Aryl Halides) (2)30/42

H. Ito et al. Nat. Commun. 2019, 10, 111.

C-H Functionalization

The Importance of C-H Functionalization

33/44✓ New & Shorter Synthetic Route

K. Itami et al. J. Am. Chem. Soc 2011, 133, 19660.
B. M. Stoltz et al. J. Am. Chem. Soc 2002, 124, 13179.

✓ Late-stage Functionalization

参考資料：文献セミナー資料（2016年12月17日、坂井）C-H Activation in Mechanochemistry

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M. Ćurić et al. Chem. Commun. 2014, 50, 10287.

First Example of Catalytic C-H Functionalization

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Solution-based reaction

F. Glorius et al. J. Am. Chem. Soc. 2010, 132, 9982.

Mechanochemical reaction

C. Bolm et al. Angew. Chem. Int. Ed. 2015, 54, 7414.

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Various C-H Functionalization in MechanochemistryRh・Olefination
・Halogenation (Br, I)・alkynylation
・amidation(C. Bolm et al. Angew. Chem. Int. Ed. 2015, 54, 7414.)(C. Bolm et al. Chem. Commun. 2015, 51, 12582.)(C. Bolm et al. Green. Chem. 2017, 19, 2520.)(C. Bolm et al. ACS Catal. 2017, 7, 4592.)

Ir・amidation
・borylation(C. Bolm et al. Angew. Chem. Int. Ed. 2016, 55, 3781.)( H. Ito et al. Chem. Eur. J. 2019, 25, 4654.)

Co・allylation
・amidation(C. Yu et al. J. Org. Chem. 2017, 82, 10665.)(C. Bolm et al. Adv. Synth. Catal. 2018, 360, 1800.)

Pd・arylation
・C-H/C-H oxidative coupling
Au・alkynylation(D.-Q. Xu et al. ACS Catal. 2016, 6, 3890.)(W.-K. Su et al. J. Org. Chem. 2016, 81, 6049.)(C. Bolm et al. Angew. Chem. Int. Ed. 2018, 57, 10723.)

1. Weakly Coordinating DG Can Work

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S. Chang et al. J. Am. Chem. Soc. 2015, 137, 4534.
C. Bolm et al. ACS Catal. 2017, 7, 4592.

2. Solvent Sensitive Metal Intermediate

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W.-K. Su et al. J. Org. Chem. 2016, 81, 6049.

2. Solvent Sensitive Metal Intermediate (2)39/44[c] comparative experiments in DMF at 100 °C, overnight
W.-K. Su et al. J. Org. Chem. 2016, 81, 6049.

2. Solvent Sensitive Metal Intermediate (3)40/44✓ m/z 542.2 cluster assigned as [Pd2(1a-H) 2(Cl) 2+H]+.
W.-K. Su et al. J. Org. Chem. 2016, 81, 6049.

2. Solvent Sensitive Metal Intermediate (4)41/44

W.-K. Su et al. J. Org. Chem. 2016, 81, 6049.

Summary of Section 3

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・Transition metal catalyzed cross coupling reactions
between solid reactants were realized by using ball milling.
・Transition metal catalyzed C-H functionalization havebeen reported since 2015.
・Most of the cross coupling reaction and C-Hfunctionalization in mechanochemistry were alreadyrealized in solution reaction.
・In mechanochemistry, it is possible to form and utilize ametal complex which is unstable to solvents.

4. Summary

Summary of Today’s Literature Seminar

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・Mechanochemical reactions have been studied fororganic synthesis mainly in the last few decades.
・Ball mills are usually used in mechanochemistry.
・Various kinds of organic reactions such as wittig reaction,
cross-coupling, C-H functionalization have been realized inmechanochemical conditions.
・ There are also some advantages in terms of reactivity.

・Mechanistic studies will lead to further progress.