1

Synthesis and Characterization of N-Heterocyclic Carbene Copper(I) Complexes.

The Catalytic Application on Huisgen Cycloaddition and Acetylation Reactions.

學生 : 李岳峰

指導教授 : 于淑君 博士

日期 : 2014. 7. 8 國立中正大學化學暨生物化學系

2

NN

Cu

N N

OTf

NNMes

Cu

N NMes

OTf

R OH Ac2O ROAc60 ¢J , neat (or 300 W, neat)

+ Cat. (2 mol%)

R1 N3 + R2

Cat. (1 mol%)

rt, neat

N

N

N

R1

R2

Acetylation of alocohol reaction

Huisgen cycloaddition reaction

Catalyst

[Cu(bmim)2](OTf) [Cu(Mesbim)2](OTf)

Outline

2

CV, XPS

3

Organometallic Catalyst

aSteven P. Nolan et al. Organometallics. 2004, 23, 1157.

Entry NHC HX‧ Time (h) Conv. (%)

1 no ligand 24 00

2 02 99

O

CuCl (3 mol%), NaOtBu (20 mol%)

NHC¡EHX (3 mol%), toluene, r.t.Et3SiH +

OSiEt3

NN

iPr

iPr BF4

iPr

iPr

3

Organometallic catalyst vs. inorganic salta

+ Metal Ligand Organometallic Catalyst

4

Choice of LigandReported – Phosphines were used as ligand of transition metals, such as Cu, Ni, Pd, Pt, Rh, Mn et al.a,b

aR. B. King et al. Inorg. Chem. 1971, 10, 1841.bVenkataraman, D. et al. Org. Lett. 2001, 3, 4315.

ex: Ni(CO)(PMe3)3 Pd(PPh3)4 Pt(PPh3)4 RhCl(PPh3)3

Entry R1 X Time (h) Yield (%)

1 H I 06 78

2 H Br 36 73

3 H Cl 36 49

Phosphines ligands enhance formation of C─N bondsb

4

N

H

+

R1

X Cu(neocup)(PPh3)Br (10 mol%)

KOtBu, toluene, 110 ¢JN

R1

5

Drawbacks – Air sensitive

P─C 、 P─OR bond were unstable at high temperaturesb

Metal leaching

Environmental pollution ─ eutrophication

Advantage – Strong σ-donating and good -accepting abilitya

Electronically and sterically tunable

PC6F5

C6F5

C6F5 P

OiPrOiPr P

o-tolyl

o-tolylo-tolylOiPr

aHerrmann, W. et al. Angew. Chem. Int. Ed. 1997, 36, 2162.bQuin, L. D. A Guide to Organophosphorus Chemistry, 2000. 5

6

N-Heterocyclic Carbenes

NNR R NNR R

N

NNR R

:

cyclic diaminocarbenes

imidazol-2-ylidenes

1,2,4-triazole-3-ylidenes

: :

NHCs PR3

the ability of -acceptinga weak strong

the ability of σ-donatinga stronger strong

the ability of oxidantionb hard easy

electronically and sterically tunable good good

environmental pollution – eutrophication

LigandProperty

The property of ligand between NHCs and PR3

aHerrmann, W. A. et al. Angew. Chem. Int. Ed. 1997, 36, 2162.bSong, W. et al. Angew. Chem. Int. Ed. 2003, 42, 892. 6

7

Choice of Metal

Price – Copper is a relatively cheaper transition metal.

The consumption and recovery of copper in the worlda

2006 2007 2008 2009 2010 2011

copper consumption (kt) 22753 23906 23841 22664 24538 25003

copper recycling (kt) 08332 08448 08611 07435 08442 08643

the percentage of copper recycling (%)

00037 00035 00036 00033 00034 00035

CuCl2 ScCl3 PdCl2 ReCl3 AgCl YbCl3 GdCl3

LD50 (mg/kg)

584 314 0200 0280 1500 300 0378

Acute toxicity

aThe International Copper Study Group 7

8

The Catalytic Applications of Cu

•O-arylation of phenols

•Diels-Alder reactions

•Acetylation of alcohols

•Asymmetric addition of dialkylzinc to imines

Cu(II)

Cu(I)•O-arylation of phenols

•Hydrosilylation of ketones

•Epoxidation reaction

•Substitution reaction

•Kharasch-Sosnovsky reaction (allylic oxidations of olefins) 8

•Oxidation of alcohols

•C─X bond formation (X = C, O, S, N)

•Friedel-Crafts alkylation reactions

•Oxidation of alcohols

•C─X bond formation (X = C, O, S, N)

•Reductive aldol reaction

•Huisgen cycloaddition

9

Acetylation of Alcohol

Application : 1. protective agent

2. medicine synthesis, ex: aspirin

3. protein acetylation

Reported apporaches :

(1) Lewis basea

aQingmin Wang et al. Org. Lett. 2014, 16, 236

O OH

OH

O OH

O

O

Ac2O

aspirinsalicylic acid

OH

Ac2O, toluene, rt, 6 h

DMAP (5 mol%)OAc

98 %

DMAP = 4-(N,N-Dimethylamino)pyridine

9

10

OH

Ac2O, CH2Cl2, rt, 0.5 h

Cu(OTf)2 (2.5 mol%)OAc

97 %

(3) Metal triflatesb

aJaved Iqbal et al. J. Org. Chem. 1992, 57, 2001bK. L. Chandra et al. Tetrahedron, 2002, 58, 1369

(2) Lewis acida

OH

Ac2O, CH3CN, 80 ¢J , 2 h

CoCl2 (5 mol%)OAc

95 %

10

[Cu(bmim)2](OTf) and [Cu(Mesbim)2](OTf) may be the first CuI complexes to catalyze acetylation of alcohol reactions.

11

Huisgen Cycloaddition

Application : 1. dye 2. photosensitive material 3. UV resistance

(1) Reduction of CuII salta

O+

sodium ascorbate, 5 mol%

H2O/BuOH, 2:1, rt, 8h

NN

NON3

CuSO4¡E5H2O, 1 mol%

91 %

aK. Barry Sharpless et al. Angew. Chem. Int. Ed. 2002, 41, 2596bFokin, V. V. et al. Org. Lett. 2004, 6, 2853

+ 1 mol % Cu(CH3CN)4PF6

H2O/t-BuOH = 1:2, rt, 24h

NN

N

84 %

N N

N BnN

3

1 mol %

N3

(2) Ligand assisted CuI saltb

11

Reported apporaches :

12

(4) NHC-CuI b

aAlonso, F. et al. Eur. J. Org. Chem. 2010, 1875.bDíez-González, S. et al. Eur. J. 2006, 12, 7558.

N3 +N

NN(SIMes)CuBr, 0.8 mol%

neat, rt, 0.3 h

98 %

+10 mol % Cu NPs

THF, 65 oC,10 min

NN

N

98 %

N3

(3) Nanosized, activated Cu(0) powdera

12

[Cu(bmim)2](OTf) 、 [Cu(Mesbim)2](OTf) Cat, (1 mol%)

neat, rt, 0.17 h>99 %

13

NHC Cu(OTf)2+ (NHC)Cu(II) complexexpected

13

Organometallic Catalyst

+ Metal Ligand + Metal Ligand + Metal Ligand + Metal Ligand

The Design of Organometallic Catalyst

However …The products are (NHC)Cu(I)─structure determined by XPS 、ESI-Mass and 1H NMR. Catalytic application : (1) acetylation of alcohols (2) Huisgen cycloaddition.

14

Motivation

1. Based on economic and conservation of environment standpoint, we use copper metal as the metal center of organometallic catalyst

2. To avoid metal leaching, we use NHC ligands to replace phosphine ligands in organometallic catalyst

3. Synthesis of NHC-CuI complexes with well defined structures

4. Using the NHC-CuI complexes to catalyze acetylation of alcohols and Huisgen cycloaddition reactions

14

15

Preparation of Copper(I) Complex Catalysts

15

Br +NN 60 ¢J / 16 hr NN

Brneat

Yield : 95 %

Preparation of (bmim)HBr

Preparation of [Cu(bmim)2](OTf)

NNBr

+ Cu(OTf)2

t-BuONa, CH3CN

r.t. / 4 hr NN

Cu

N N

OTf

Yield : 60 %

2 eq 1 eq

6 eq

1616

Preparation of 1-mesityl-1H-imidazole

Preparation of [Cu(Mesbim)2](OTf)

NNMes

OO

NH2

+

1. HCHO / NH4OAc / HOAc / H2O 70 oC / 18 hr

2. NaHCO3 / H2O, 1 hr

NN Mes

Br + Cu(OTf)2

t-BuONa, CH3CN

r.t. / 4 hr NNMes

Cu

N NMes

OTf

Yield : 55 %Preparation of (Mesbim)HBr

NN Mes + Br

CH3CN

82 oC / 24 hr

NNMes

Br

Yield : 92 %

Yield : 61 %

2 eq 1 eq

6 eq

1717

1H NMR Spectra of (bmim)HBr and [Cu(bmim)2](OTf)

NN

Cu

N N

OTf

H1

H2

H3

NN

Br

H1

H2

H3

H4 H4

(bmim)HBr

[Cu(bmim)2](OTf)

*

*#

* CHCl3

# H2O

1818

13C NMR Spectra of (bmim)HBr and [Cu(bmim)2](OTf)

NN

Br

NN

Cu

N N

OTf

C1

C1

C2

C2

(bmim)HBr

[Cu(bmim)2](OTf)

* CDCl3

*

1919

1H NMR Spectra of (Mesbim)HBr and [Cu(Mesbim)2](OTf)

NN

Br

H1

H2

H3

H4

(Mesbim)HBr

H5

H6

[Cu(Mesbim)2](OTf)

NNMes

Cu

N NMes

OTf

2020

13C NMR Spectra of (Mesbim)HBr and [Cu(Mesbim)2](OTf)

NN

Br

C1

(Mesbim)HBr

[Cu(Mesbim)2](OTf)

NNMes

Cu

N NMes

OTf

2121

IR Spectra of (bmim)HBr and [Cu(bmim)2](OTf)

NNBr

NN

Cu

N N

OTf

1226 cm-1

(H─C─C & H─C─N bending)

1169 cm-1 (H─C─C & H─C─N bending)

(bmim)HBr

[Cu(bmim)2] (OTf)

Cu(OTf)2

2222

IR Spectra of (Mesbim)HBr and [Cu(Mesbim)2](OTf)

NNMes

(Mesbim)HBr

Br

(Mesbim)HBr

NNMes

[Cu(Mesbim)2](OTf)

Cu

N N MesOTf

[Cu(Mesbim)2](OTf)

Cu(OTf)2

1201 cm-1 (H─C─C & H─C─N bending)

1226 cm-1 (H─C─C & H─C─N bending)

2323

[Cu(bmim)2](OTf) (mol/mg) [Cu(Mesbim)2](OTf) (mol/mg)

Calculated (Cu : L = 1:1)

2.85 * 10-6 2.19 * 10-6

Calculated( Cu : L = 1:2)

2.05 * 10-6 1.44 * 10-6

Experimental 1.86 * 10-6 1.31 * 10-6

NN

Cu

N N

OTf

Atomic Absorption Spectral Data of [Cu(bmim)2](OTf) and [Cu(Mesbim)2](OTf)

NNMes

Cu

N N Mes

OTf

2424

ESI-Mass Spectral of [Cu(bmim)2](OTf)

242.06

339.20

NN

Cu

N N

2525

NN

CuCH3CN

2626

ESI-Mass Spectral of [Cu(Mesbim)2](OTf)

547.37

NN

Cu

N N

2727

CuI (2p3/2) : 932 ~ 935 Va

CuII (2p3/2) : 935 ~ 938 V

X-Ray Photoelectron Spectral of [Cu(Mesbim)2](OTf) and Cu(OTf)2

aFrost, D. C. et al. Mol. Phys. 1972, 24, 861.

932 V

935 V

[Cu(Mesbim)2](OTf)

Cu(OTf)2 satellite

satellite

2828

Cyclic Voltammetry of [Cu(Mesbim)2](OTf)

0.805 V (oxidation peak)

NNMes

Cu

N N Mes

OTf

Reporteda

aKieltsch, I. et al. Organometallics 2010, 29, 1451.

NN

Cu

X = CH3, 0.65 V (oxidation peak) CF3, 1.24 V (oxidation peak)

X

29

2Cu(OtBu)2 + 4NaOTf2Cu(OtBu)2 2Cu(OtBu) + tBuO¢wOtBu

4(bmim)HBr 4bmim (NHC carbene) + 4NaBr + 4HOtBu

4bmim (NHC carbene ) + 2Cu(OtBu) 2[Cu(bmim)2][OtBu]

2[Cu(bmim)2][OtBu] + 2NaOTf 2[Cu(bmim)2][OTf] + 2NaOtBu

4NaOtBu2Cu(OTf)2

4NaOtBu

¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w¢w2Cu(OTf)2 + 6NaOtBu + 4(bmim)HBr 2[Cu(bmim)2][OTf] + tBuO¢wOtBu

+ 4NaBr + 2Na(OTf) + 4HOtBu

Copper reduction

(1)

(2)

(3)

29

Cu O +O O

2CuO O2

150 ¢J thermodynamic stability

Reporteda

aTsuda, T. et al. J. Am. Chem. Soc. 1972, 94, 658.

Reduction Mechanism from CuII to CuI

2

2

Proposed mechanism for catalyst synthesis

3030

R OH Ac2O ROAc60 ℃, 3 hr, neat+

Cat. (2 mol%)

EntryAlcohol or

Phenol

[Cu(bmim)2](OTf) [Cu(Mesbim)2](OTf)

Yield (%) Yield (%)

1 98 99

2 98 99

3 92 95

4 97 98

5 59 60

6 35 42

OH

OH

OH

HO

HO

OH

5

NHC-CuI Catalyzed Acetylation Reactions of ROH with Acetic Anhydride

3131

EntryAlcohol or

Phenol

[Cu(bmim)2](OTf) [Cu(Mesbim)2](OTf)

Yield (%) Yield (%)

7 97 95

8 98 99

9 97 96

10 99 99

11 99 99

12 98 97

13 92 95

R OH Ac2O ROAc60 ℃, 3 hr, neat+

Cat. (2 mol%)

OH

OHMeO

O2NOH

OH

OH

I

OH

OH

3232

Entry Alcohol or Phenol[Cu(bmim)2](OTf)

Yield (%)

1 90

2 93

3 95

4 92

5 90

6 93

OH

OH

OH

I

OH

O2NOH

OHMeO

OH

R

+ Ac2OCat. (2 mol%)

60 ¢J, 1.5 hr, neat

OAc

R

333333

Entry Alcohol or Phenol[Cu(Mesbim)2](OTf)

Yield (%)

1 75

2 77

3 85

4 77

5 74

6 66

OH

OH

OH

I

OH

O2NOH

OHMeO

OH

R

+ Ac2OCat. (2 mol%)

60 ¢J , 1 hr, neat

OAc

R

3434

R O R

O O

R O R

O OMn+

R'OHMn+

PhCH3

R O

OR'

R = MeMn+ = Na+

Reported Mechanisms for Acetylation of Alcohols

Mechanism (i)a

Mechanism (ii)b

aWack, H. et al. Org. Lett. 1999, 1, 1985.bK. L. Chandra et al. Tetrahedron, 2002, 58, 1369.

ROAc + HOAcROH

Cu(OTf)2AcOTf + Cu(OTf)OAc

detectable

Ac2O

3535

Proposed Mechanism for Acetylation of Alcohols

[Cu(bmim)2](OTf)Ac2O

O

O O

L2Cu

O

O O

L2Cu

OTf

O

L2Cu

TfO

O

O ROH

R OH

O

L2Cu

TfOO

RH

O O

AcOH + ROAc

OTf

3636

Convection transition

Thermal vs. Microwave Heating

Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.

microwave thermal

3737

HO

NHC-CuI Catalyzed Acetylation Reactions of ROH with Acetic Anhydride under MW Irradiation

R OH Ac2O ROAc+Cat. (2 mol%)

60 ¢J or MW (300 W)

EntryAlcohol or

Phenol

[Cu(bmim)2](OTf) [Cu(Mesbim)2](OTf)

Thermal (3 h)

MW (30 s)

Thermal(3 h)

MW (30 s)

Yield (%) Yield (%) Yield (%) Yield (%)

1 98 99 99 99

2 98 99 99 99

3 92 89 95 96

4 97 97 98 99

5 59 94 60 82

6 35 65 42 61

OH

OH

5

OH

HO

OH

3838

EntryAlcohol or

Phenol

[Cu(bmim)2](OTf) [Cu(Mesbim)2](OTf)

Thermal (3 h)

MW (30 s)

Thermal(3 h)

MW (30 s)

Yield (%) Yield (%) Yield (%) Yield (%)

7 97 93 95 95

8 98 99 99 99

9 97 97 96 99

10 99 99 99 99

11 99 99 99 99

12 98 99 97 98

13 92 97 95 97OH

OHMeO

O2NOH

OH

OH

I

OH

OH

R OH Ac2O ROAc+Cat. (2 mol%)

60 ¢J or MW (300 W)

39

EntryCatalyst

Cat Conc.(mol %)

MW (W)

Time (min)

Yield(%)

1A PPTS (Pyridinium p-toluenesulfonate)

100 700 3 94a

2B NaOH 12.5 530 4 96b

3 [Cu(bmim)2](OTf) (2) 2 300 0.5 97c

4[Cu(Mesbim)2](OTf)

(5) 2 300 0.5 97c

Reaction condition :a alcohol : Ac2O (1 : 1.5), solvent = neat, b alcohol : Ac2O (1 : 2),

solvent = neat, c alcohol : Ac2O (1 : 8), solvent = neat.

OH Ac2O OAc

neat

Reported

AJong Chan Lee et al. Bull. Korean Chem. Soc. 2004, 25, 1295. BPatnam, R et al. Journal of Chemical Research 2002, 301.

39

4040

NHC-CuI Catalyzed Huisgen Cycloaddition

R1 N3 + R[Cu(bmim)2](OTf) (1 mol%)

rt, neat

N

N

N

R1

N3

N3

Entry Azide

Time (min) Yield (%) Time (h) Yield (%)

1 10 >99 1.5 >99

2 10 >99 1.5 >99

3 10 >99 1.5 >99

4 10 >99 1.5 >99

5 10 >99 1.0 >99N3

Br

N3

N3

4141

N3

N3

Entry AzideT

(℃)Time (min)

Yield (%)

T(℃)

Time (h)

Yield (%)

1 rt 10 >99rt 1.5 >41

50 1.0 >99

2 rt 10 >99 50 1.0 >99

3 rt 10 >99 50 1.0 >99

4 rt 10 >99 50 1.0 >99

5 rt 10 >99 50 0.5 >99N3

Br

N3

N3

R1 N3 + R[Cu(Mesbim)2](OTf) (1 mol%)

neat

N

N

N

R1

4242

Mechanism for Huisgen Cycloaddition

[Cu(bmim)2](OTf)PhH

(bmim)Cu Ph

(bmim)Cu Ph

NN

NBn

NN

N

Ph

Bn

Cubmim

(bmim)Cu

NN

NBn

Ph

NN

NBn

Ph

(bmim)HOTf

(bmim)HOTf

BnN3

pKa : 19

pKa : 25

4343

Conclusions

1. We have successfully synthesized [Cu(bmim)2](OTf) and [Cu(Mesbim)2](OTf) complexes. Their structures were characterized

by using 1H- and 13C-NMR, IR, AAS, XPS, ESI-Mass and CV spectroscopy.

2. We have successfully demonstrated the catalytic activity of [Cu(bmim)2](OTf) and [Cu(Mesbim)2](OTf) on the acetylation of

alcohol and Huisgen cycloaddition reactions.

3. Further acceleration on the rate of the [Cu(bmim)2](OTf)─and [Cu(Mesbim)2](OTf)─catalyzed acetylation of alcohols can be achieved under microwave irradiation conditions.

4444

謝誌

指導老師 : 于淑君 博士

口試老師 : 梁 孟 博士 曾炳墝 博士

實驗室成員 : 張朝欽、陳思婷、潘慶豪、 王建舜、林羲尹、謝承祐

無機組全體成員