Ionic Liquids in Organic Synthesis Adam M. Azman 15 November 2006 15 November 2006

Ionic Liquids

AMA 1

What is an Ionic Liquid? • Any salt above its melting point • Technically, all molten salts, such as NaCl (mp = 800oC), are ionic liquids • Obviously not practical for organic synthesis

15 November 2006

Ionic Liquids

AMA 2

What is an Ionic Liquid? • Definitions from Literature – –

– – –

“The term ionic liquid implies a material that is fluid at (or close to) ambient temperature, is colorless, has a low viscosity and is easiliy handled.” (Sheldon) “Room temperature ionic liquids are generally salts of organic cations, e.g. tetraalkylammonium, tetraalkylphosphonium, N-alkylpyridinium, 1,3-dialkylimidazolium and trialkylsulfonium cations.” (Sheldon) “Most basic definition of a room temperature ionic liquid is a salt that has a melting point at or near room temperature.” (Handy) “Organic salts with melting points below ambient or reaction temperature.” (Maio) “Ionic liquid is a salt with a metling temperature below the boiling point of water.” (Wilkes)

– Salt of organic cation which has a melting point near ambient temperature (up to ~100oC) H Al2 Cl7

AlCl3 N Cl

R H

Et 3 NHCuCl2

N

N PF6

15 November 2006

Ionic Liquids

AMA 3

Synonyms for Ionic Liquids • • • • • • • • •

Ionic Liquid (IL) Room temperature ionic liquid (RTIL) Molten salt Room temperature molten salt Ambient temperature molten salt/ionic liquid Task specific ionic liquid (TSIL) Liquid organic salt Fused salt Neoteric solvent

15 November 2006

Ionic Liquids

AMA 4

A •

(very)

1800s – So called “red oil” formed during Friedel-Crafts reactions –

•

AlCl3 N

o

Melting point = 40 C, butylpyridinium cation easily reduced

Cl-

Large, asymmetric anions should lower melting point, as should large, asymmetric cations

Imidazolium theorized to be excellent candidate (experimentally true) Imidazolium cation more stable to reduction, melting point below room temperature

R N

N R

Chloroaluminate salts are reactive to water – not a problem for batteries –

•

Thermal batteries have molten salt electrolyte (LiCl-KCl) Reaches temperatures between 375-550oC

1970s – Fast computer method (1 week) for predicting electrochemical properties of ammonium salts – –

•

Al2 Cl7 -

It was noticed that large anions with many degrees of freedom inhibited crystalization until lower temperature –

•

R H

Ethylammonium nitrate (1914) has melting temperature of 12oC Used as liquid propellants for naval guns

Start of modern era of ionic liquids began with discovery of 1butylpyridinium chloride-aluminum chloride mixture –

•

Identified as long presumed intermediate called sigma complex

1960s-Present – Air Force Academy has continuous research effort for ionic liquds for thermal batteries – –

•

H

Early 1900s - Alkylammonium nitrates found to be liquids at room temperature – –

•

Brief History of Ionic Liquids

Early 1990s – Ethylmethylimidazolium halides prepared, then anion metathesis with various silver salts provided a small library of room temperature ionic liquids

Late 1990s-Present (and beyond) – Envelope (as always) being pushed – –

Exotic anions, functionalized cations, functionalized anions, chiral cations/anions, … Limitless possibilities of new ionic salts to fill every niche of chemistry

15 November 2006

Ionic Liquids Wilkes, J. S. Green Chemistry, 2002, 4, 73-80

AMA 5

Properties • • • • • • • • • • • •

Non-flammable Negligible vapor pressure High thermal/chemical/electrochemical stability Solvating ability Large liquidus range (span of temperatures between melting and boiling point of a liquid) Easy recyclability Highly polar Non-coordinating Tunable miscibility with water or organic solvents Generally do not coordinate with metals, enzymes Able to be stored for long time without decomposition Chiral ionic liquids may control stereoselectivity “Pure imidazolium ionic liquids can be described as polymeric hydrogenbonded supramolecules and in some cases when mixed with other molecules, they should better be regarded as nonstructured materials with polar and non polar regions rather than homogeneous solvent.” (Dupont)

15 November 2006

Ionic Liquids

AMA 6

Properties •

Stability/Thermal decomposition – Imidazolium cation stable above 300oC – Decomposition: cleavage of C-N bond between imidazole nitrogen and alkyl chain – Anion plays a role • Less nucleophilic – higher stability

•

Density – – – –

•

Least effected by temperature variation or impurity All greater than 1 for imidazolium cation Lengthening alkyl chain – lower density Increasing halogen content – higher density

Viscosity – Even least viscous room temperature ionic liquids are quite viscous compared to conventional solvents – Highly sensitive to temperature and impurities – Short alkyl chain/functionalized alkyl chain – lower viscosity • Longer alkyl chain – increased van der Waals forces – increased energy required for molecular motion

•

– BF4- anion causes lower viscosity than PF6- anion

Conductivity

– Inversely parallels viscosity 15 November 2006

Ionic Liquids

AMA 7

The Cation • Infinite in number • Most common: – – – –

R

R

Dialkylimidazolium N N N R Alkylpyridinium R Tetraalkylammonium R N R R R Tetraalkylphosphonium R PR R

• Can be tuned to properties needed • For liquid at room temperature, should be unsymmetrical – Functionalizing side chain on cation can change melting point of straight-chain relative – Presence of C2-methyl group generally increases melting point of unsubstituted relative – Substituting at C4 has little effect on melting point 15 November 2006

Ionic Liquids

AMA 8

The Anion • Much diversity – Common: • • • • •

F F B- F

Tetrafluoroborate F Hexafluorophosphate FF P FF F Bis(trifluoromethanesulfonyl)imide Halogen Mesylate/tosylate/triflate F

-

O

O S O

O F F

OO O S F N F F F

S

O

O S O

O F -

O S F O F

• Larger, more weakly coordinating anion – lower melting temperature

15 November 2006

Ionic Liquids

AMA 9

Melting Point Variation BF4

Melting point for R Methyl Imidazolium Cation with Varying Anion

Br Cl

250

Me N

Ms NTf2

200

R methyl imidazolium cation [Rmim][X]

PF6 Melting Point (deg C)

N R X-

Tf

150 100 50 0 0

2

4

6

8

10

12

14

16

18

20

-50 -100 Le ngth of Alkyl Cha in (# Ca rbon Atom s)

Melting Points for Symmetrical Ionic Liquids (PF6 Anion) 120 100

Melting Point (deg C)

80

R N

N R PF6 -

symmetrically substituted imidazolium cation [RRim][PF6 ]

15 November 2006

Ionic Liquids

60 40 20 0 -20 0

1

2

3

4

5

6

7

8

9

-40 -60 -80 -100 # Carbon atoms (per side)

AMA 10

10

Partial Miscibility Chart (R Methyl Imidazolium Cation)

15 November 2006

Ionic Liquids

AMA 11

Other Ionic Liquid Cations • Pyridinium – Possibly unstable in presence of nucleophiles – Alkyl chain length effect on melting point mirrors imidazolium

• Tetraalkylammonium – Known for much longer than imidazolium – Highly viscous/difficult to handle – Long alkyl chain/decreased symmetry – lower melting point

• Others – Triazolium, pyrazolium, thiazolium, benzimidazolium – Guanidinium, phosphonium, sulfonium 15 November 2006

Ionic Liquids

AMA 12

“Synthesis”

15 November 2006

Ionic Liquids

AMA 13

Why do I care? •

“Problems” with molecular solvents: – – – – – – – – –

Grant money becoming more competitive Chemical “bunker” a real inconvenience Toxic/hazardous properties of solvents, notably chlorinated hydrocarbons Expensive catalysts Strong acids High temperatures Long reaction times Possible cumbersome isolation procedures Other drives to anchor catalyst for recovery/reuse require additional catalyst/enzyme modification • Steric hindrance causes decrease in efficiency of reaction

•

“Solutions” with ionic liquids: – Combine best advantages of molten salts and avoid worst disadvantages caused by high temperatures – Two phase system allows product in one phase, everything else in other phase – Ionic liquid immobilizes catalyst/reagent for recycling and reuse – Ionic liquids can act as solvent and catalyst in some systems without need for additional catalyst or ligand – Rate acceleration effect on some catalytic reactions

15 November 2006

Ionic Liquids

AMA 14

Limitations • • • • •

A “dearth” of information on biodegradability and toxicity Cannot be purified by distillation Trace impurities can have significant impact on physical properties– must be initially produced in high purity Some ionic liquids are prone to hydrolysis – especially in reactions involving metals C2 hydrogen relatively acidic (pKa = 21-23) – –

• •

Deprotonation generates N-heterocyclic carbene Good ligand for metal complexes

Oxidative addition to electron-rich Ni0 or Pd0 to generate (carbene)metal hydride compounds Decomposition possible under sonochemical conditions – –

Creates hot spots in solvent May limit ultrasound- and microwave-assisted processes

15 November 2006

Ionic Liquids

AMA 15

Applications • • • • •

Storage media for toxic gases Lubricants Performance additives in pigments Propellants Organic chemistry: •Hydrogenation

•Wittig

•Hydroformylation

•Robinson annulation

•Alkoxycarbonylation

•Dihydroxylation

•Cross coupling (Heck, Suzuki, Negishi, Stille)

•Alcohol oxidation

•Allylic substitution

•Friedlander reaction

•Friedel-Crafts alkylation

•Nitration of phenols

•Diels-Alder

•Bromination of aromatics/alkynes

•Diol/carbonyl protection

•Cyclopropanation

•Epoxidation/Epoxide opening

•Synthesis of 2,4,5-triaryl imidazoles

•Cyanosilyation of aldehydes

•Synthesis of 3,4-dihydropyrimidin-2(1H)ones

•Esterification

•Dimer-/Oligomer-/Polymerization

•Ring closing metathesis

•Chiral solvent for asymmetric synthesis

•Knoevenagel condensation •Baylis-Hillman 15 November 2006

•Kinetic resolution Ionic Liquids

•Biocatalysis

AMA 16

Diol/Carbonyl Protection R3 O R1

• • •

HO

R3

OH

[Hmim][BF4 ] 90 °C

R1

R2

HN

N Me BF4 -

[Hmim][BF4-]

In molecular solvents – large excess of reagents Monosubstituted imidazolium ionic liquids serve as Brønsted acids Acidic ionic liquids afford protected product with: – – – – –

•

R2

O O

No added catalyst 1:1 ratio of carbonyl to diol No refluxing/Dean-Stark trap No molecular solvent Recyclable catalyst

Acetals immiscible with ionic liquid – no need to remove water

15 November 2006

Ionic Liquids Wu, H-H.; Yang, F.; Cui, P.; Tang, J.; He, M-Y. Tetrahedron Lett., 2004, 45, 4963-4965.

AMA 17

Diol/Carbonyl Protection R3 O R1 C a rb o ny l

HO

R2 A lc oh o l

R3

O O OH

[H m im ][B F 4] 9 0° C

M o la r R ati o Ti me (h )

R1

R2

Se l ec ti vi ty (% )

C on ve rs io n (% )

O n

hex

H

HO

OH

1:1

3

100

98

HO

OH

1:1

3 .5

100

100

HO

OH

1:1

6

100

93

HO

OH

1:1

6

100

76

1:1

6

100

93

1:1

6

100

100

OH

1:1

6

100

97

OH

1:1

6

100

94

OH

1:1

3

100

OH

1:2

3

100

100

OH

1:2

6

100

60

OH

1:2

6

100

100

O O

O O Ph

H O H

HO

OH

HO

OH

HN

N

BF 4 -

[Hm im ][BF 4 ]

NO 2 O nh e x

H

HO

O HO O HO O

HO

O Ph

HO

H O H

HO

92

92

94

94

94

95

94

95

94

NO 2

15 November 2006

Ionic Liquids Wu, H-H.; Yang, F.; Cui, P.; Tang, J.; He, M-Y. Tetrahedron Lett., 2004, 45, 4963-4965.

AMA 18

Friedlander Synthesis O

R1 R1

O R2

R2

R3

NH 2

• • •

N

Common additives: HCl, H2SO4, PTSA, microwave, ZnCl2/NEt3, ruthenium or palladium complexes Can be run in ionic liquid with no additive Efficacy correlated to basicity of anions of ionic liquid Bu N

N Bu X-

[bbim][X]

HN

N Bu X-

[Hbim][X]

•

R3

Ionic Liquid

pKa of Acid of Anion, HX

Yield (%)

[bbim][ClO4] [bbim][Br] [bbim][Cl] [bbim][PF6] [bbim][BF4]

-11 -9 -7

37 50 50 70 75

[Hbim][ClO4] [Hbim][Br] [Hbim][Cl] [Hbim][PF6] [Hbim][BF4]

-11 -9 -7

0.5

0.5

50 75 73.8 90 96

Ionic liquid can be recovered almost completely and recycled at least twice

15 November 2006

Ionic Liquids

Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.; J. Org. Chem., 2003, 68, 9371-9378.

AMA 19

Friedlander Synthesis

OH

OH

O H

O H

N

NH 2

N

NH 2 O Me

H

H

H

H O

O

O

N H N

N H N H O

H

N O

H

N

N

O

H

H

N

N

H

Ar

15 November 2006

O

H

O

H

O

H

N

H

H N N

Ionic Liquids Muchowski, J. M.; Maddox, M. L.; Can. J. Chem., 2004, 82, 461-478.

AMA 20

O H

Friedlander Synthesis O

R1 R1

Co m po u nd 1

O R2

NH2 C om p ou n d 2

A B -

R 1 =H, R 1 =Cl,

O

R2

A B

N H2 R 2 =Me R 2 =Ph

O OE t

O

O

N R2

Me O

OE t

R1

Me

Me

A B

R2 R1

Me

O

[H b im ][BF 4 ]

Pro d u ct

O R1

R2 R3

O

Me

N Tim e (h )

O

A 94 93 B 94 94

93 93

3.3

A 94 94 B 93 93

93 91

N Me R2

HN

R1 3

A 96 95 B 97 96

94 95

3

A 96 96 B 98 96

94 96

O

3

A 97 96 B 97 95

95 95

O

4

A 94 94 B 93 92

93 91

N R2

6

A 93 92 B 91 90

90 90

3.3

A 93 93 B 93 93

91 92

R1

A B

N R2

O Me

Me

O

R1

Me N R2

Me

R1

Me

Ph N

15 November 2006

[H b im ][BF 4 ]

R1

A B

A B

N Bu BF 4-

R1 N R2

A B

Yi e ld (% )

3

N R2 A B

R3

Me

Ionic Liquids

Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.; J. Org. Chem., 2003, 68, 9371-9378.

AMA 21

Knoevenagel Condensation/ Robinson Annulation EWG

• • •

EWG

EWG

O R

H

EWG

R

Reactions performed in air without rigorous drying of ionic liquid Product extracted with toluene Ionic liquid washed with toluene and reused without further purification

15 November 2006

Ionic Liquids Morrison, D. W.; Forbes, D. C.; Davis, Jr., J. H. Tetrahedron Lett., 42, 2001, 6053-6055. Forbes, D. C.; Law A. M.; Morrison, D. W. Tetrahedron Lett., 47, 2006, 1699-1703.

AMA 22

Knoevenagel Condensation/ Robinson Annulation O EWG

R M al on a te D e riv ati ve

NC

H

[h ex mi m][PF 6 ] 22 h , 4 5 -5 5° C

C ar bo n yl D e ri va tive Cl

E WG

R Yi e ld (% ) (u no p tim ize d )

Pr od u ct

H

CN

EWG

gl yci n e (0 .2 e q .)

E WG

CN

O Cl

86

CN

CN

O

CN O 2N

CN

O

77

CN

CN

CN

O M eO

OH

74

H NC

O

CN

O 2N

CN

PF 6-

g ly cin e

H NC

n h ex

H 2N

H NC

N

[h e xm im ][P F 6 ]

Cl

Cl

Me N

62

“10 cycles performed without dropping below 90% conversion.”

CN

Me O H

NC

CN

CN

O

32

CN O O EtO

15 November 2006

O

O

O

EtO

48

Me

Ionic Liquids Morrison, D. W.; Forbes, D. C.; Davis, Jr., J. H. Tetrahedron Lett., 42, 2001, 6053-6055. Forbes, D. C.; Law A. M.; Morrison, D. W. Tetrahedron Lett., 47, 2006, 1699-1703.

AMA 23

Hydrogenation • •

First example by Chauvin, 1995 Dupont showed RuCl2(Ph3P)3 in [bmim][BF4] has turnover number = 540 h-1 –

Metal complex recyclable H2 C O 2H

C ata ly st

Su b stra te

i n s it u R u -(S )-BIN AP

[R uC l 2- (S)- BIN AP ]2 • N Et 3 i n s itu R u -(R )-B IN A P

(S)

C O 2H

Ph Ph

[R uC l 2- (S)- BIN AP ]2 • N Et 3

Ph (S)

1 st re cyc le

Ph

2 nd re cy cle

C O 2H

Ph

3r d re c ycl e

Ph (S)

[R u -(S )-BIN AP ] M eO

100

62 (S)

M e OH

100

83 (S)

i -PrO H

100

64 (S)

[b mi m][BF 4 ]/Me OH

100

86 (S)

[b mi m][B F 4]/i -P rOH

99

6 9 (R )

[b mi m][B F 4]/i -P rOH

99

7 2 (R )

[b mi m][B F 4]/i -P rOH

99

7 7 (R )

[b mi m][B F 4]/i -P rOH

99

7 0 (R )

[b mi m][B F 4]/i -P rOH

100

78 (S)

[b mi m][B F 4]/i -P rOH

100

84 (S)

[b mi m][B F 4]/i -P rOH

90

79 (S)

[b mi m][B F 4]/i -P rOH

95

67 (S)

[b mi m][B F 4]/i -P rOH

100

80 (S)

PH 2 PH 2

B INA P

(R)

3r d re c ycl e

M e OH

Ph

Ph

2 nd re cy cle

% ee

Ph

Ph

1 st re cyc le

C on v er sio n (% )

C O 2H

Ph

i n s itu R u -(R )-B IN A P

So l ve nt Sy ste m

Pro d uc t

Ph

[R uC l 2- (S)- BIN AP ]2 •N Et 3

* C O 2H

[R u- BIN AP ] [b mi m][BF 4 ]/Org a n ic S ol ve nt

C O 2H

Me

N

N B F 4-

[bm im ][B F 4 ]

M eO (S)- Na p ro xe n

15 November 2006

Ionic Liquids

Monteiro, A. L.; Zinn, F. K.; de Souza, R. F.; Dupont, J. Tetrahedron: Asymmetry, 1997, 8, 177-179.

AMA 24

Diels—Alder •

Ionic liquid allows for catalyst recovery, rate acceleration, selectivity enhancement O

O S c(OTf )3 ( 0.2 mo l% ) s ol ve n t, rt, 2 h

O

O Yi el d ( % ) 22 46 >99

S ol ve nt C D 2 C l2 [bm im ][PF 6 ] ( 1 e q .) + C D 2 Cl 2 [bm im ][PF 6 ] Di e no p hi le

Di e ne

Pr od u ct

O

Y ie ld (% )

>99 :1

94

[bmim][PF6 ]

O -

O

94

>99 :1

96

-

80

>99 :1

84

>99 :1

71

86 83

81 87

88 89

86 91

85 90

O O

O O

O

O O

O

O O O

O

N Bu PF6 -

O

O

O

Me N

O

O

15 November 2006

En d o :ex o

O O

O

O

O

O

O

O

Ionic Liquids

Song, C. E.; Shim, W. H.; Roh, E. J.; Lee, S.; Choi, J. H. Chem. Commun., 2001, 1122-1123.

AMA 25

Olefin Epoxidation • • • •

(R,R)-Jacobsen’s catalyst immobilized in ionic liquid Rate enhancement noticed over molecular solvents Enantioselectivity and activity decrease upon reuse – possible catalyst degredation over time Co-solvent used for reactions below room temperature, because ionic liquid solid at reaction temperature

H

H N

N Mn

t-Bu

O t-Bu

Cl

O

t-Bu

t-Bu

(R,R)-Jacobsen's Catalyst

15 November 2006

Ionic Liquids

AMA 26

Olefin Epoxidation R1

R3

(R, R)-Jacobsen's Catalyst NaOCl

R2

R4

[bmim][PF 6]-CH2 Cl2 0 °C

Substrate

Product

O R1

R2

R3 R4 Me N

Time (h)

Yield (%)

% ee

2

86 73 73 60 53

96 90 90 89 88

4

72

94

N Bu PF6 -

[bmim][PF 6]

O

O

O O

O NC

NC

H

O 4

72

Ph

O

84

t-Bu

O Me

N Mn

t-Bu

Ph

H N Cl

O

t-Bu

t-Bu

(R,R)-Jacobsen's Catalyst

Me 3

72

86

4

77

84

O O

15 November 2006

Ionic Liquids Song, C. E.; Roh, E. J. Chem. Commun., 2000, 837-838.

AMA 27

Heck Reaction •

1996 – First example in ionic liquid by Kaufmann –

• •

Used ammonium and phosphonium salts

Ph

Br Pd

Under basic conditions, deprotonation and formation of palladium Br complexes of imidazolium carbenes facile N Me Competition of cationic and neutral pathways for enol ethers nonexistent in ionic liquids – α-arylation (cationic) regiospecific +

Pd P P I

BuO

N N Me

IPh

OBu P Pd P

Ph

Ph

OBu

I

Pd P

OBu

Ph

BuO Ph Pd P

P

P Pd P

I

Ph

Ph

OBu

I

1999 – Seddon found tri-phasic system – organic: product, ionic liquid: catalyst, aqueous: salt –

•

Bu

OBu

Bu N

P

•

O

Allows catalyst to be recovered and reused

Similar results for Suzuki, Stille, and Negishi (although yield decreases on recycle experiments for Negishi)

15 November 2006

Ionic Liquids

AMA 28

Heck Reaction D PP P (2 eq .) N Et 3 (1 .2 e q) P d( OAc )2 ( 2.5 mo l% )

A rX

OBu

[b m im ][B F 4 ], 1 00 ° C , 1 8 h

Ar

OBu !

Su bs tra te

Te mp e ra tur e (° C )

Tim e (h ) C o nv er sio n (% )

OB u

Ar " !/ "

Y ie ld (% )

Br 10 0

24

100

>9 9 /1

95

80

24

100

>9 9 /1

94

I

Ph2 P

Br 11 0

36

100

>9 9 /1

94

12 0

36

100

>9 9 /1

90

PPh2 DPPP

NC Br M eO 2C Br Me

12 0

36

100

>9 9 /1

92

10 0

24

100

>9 9 /1

93

12 0

24

100

>9 9 /1

97

10 0

24

100

>9 9 /1

95

12 0

36

100

>9 9 /1

88

Me N

N

BF4 -

[bmim][BF4]

O Br H O Br F Br

Br Me

15 November 2006

Ionic Liquids Xu, L.; Chen, W.; Ross, J.; Xiao, J. Org. Lett., 2001, 3, 295-297.

AMA 29

Swern Oxidation •Ionic liquid tethered “dimethyl sulfoxide” can be prepared with no chromatography and no volatile (read: smelly) organosulfur reagents •Products separated from ionic liquid by phase extraction with ether •Reduced sulfide may be reoxidized and reused for at least 4 recycles with small loss of activity •Also able to tether TEMPO catalyst 1)

Br

OH N

! N

N TfO -

OH

2 ) Ag OTf, Me C N

M sC l C s2 C O 3

S 1)

Me C N

N

H2 N

H 5 IO 6

N H2

M eC N N

N TfO -

OMs

2 ) N a OH /H2 O 3 ) M e2 S O 4

98% N

N TfO

O

S

9 4% 6 s te p s no ch ro ma to gr ap y

N

S

TfO -

- 78 ° C O

15 November 2006

N

(C OC l)2 , NE t 3 C H 2C l 2/M eC N

-

Ionic Liquids He, X.; Chan, T. H. Tetrahedron, 2006,62, 3389-3394

OH

AMA 30

Swern Oxidation H5 IO 6 N

N

S

N

(COCl)2 , NEt3 CH 2Cl2/MeCN

TfO -

O S

N TfO -

-78 °C O

OH

Substrate

Product

OH

Yield(%)

O 90 OH

OH

81

H

88

H

95

O

H OH

86

O

H

BnO

87

BnO

O 82

O Me Me

O Me Me

Me

Me

O

90

OH

15 November 2006

Ionic Liquids He, X.; Chan, T. H. Tetrahedron, 2006,62, 3389-3394

AMA 31

RCM •

Simple dissolution of catalyst not effective – catalyst soluble in organic solvents & decomposes

HO

O

O

OMe

Br

1 ) N aH , iP rI, D MF 9 0% 2 ) Br2 , H OAc , C H 2 C l2 , 9 8 % 3 ) Li Al H 4, TH F, 95 %

1 ) 1- me thy li mi da zo l e, Ph M e 2 ) H PF 6 , H2 O, 8 7% - 2 step s 3 ) 1, C u Cl , CH 2 C l2 , 78 %

Br O

Cl Cl

HO

P Cy 3 Ru

1) B u3 S nC H C H 2, Pd (P Ph 3 )4 , P hM e , 7 5 % 2) N Et 3 , Ms Cl , CH 2 C l2 3) L iB r, TH F, D M F, 7 4 % - 2 s te p s

PF 6 - N

N

O

15 November 2006

Ionic Liquids

Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J-C. J. Am. Chem. Soc., 2003, 125, 9248-9249.

Cl Cl

P Cy 3 Ru P Cy 3Ph 1

AMA 32

Ring Closing Metathesis R Cl Ru Cl

PF6-

N N

O R

[bmim][PF6 ], 60 °C

R

! 5 mol% cat. ! 4h R

Substrate Ts N

PCy3 Ts N

Product Ts N

Ts N

PCy3

Ts N

sIMesa

Ts N

Conversion(%)

>98

>98

>98

>98

>98

>98

97

92

N

>98

>98

>98

96

93

91

80

>98

>98

>98

>98

>98

>98

95

N

[bmim][PF6 ]

95 Mes N

EtO 2C CO2 Et

EtO2 C CO 2Et

sIMes (25°C)a O PCy3

a

>98

>98

>98

94

78

48

>98

>98

>98

83

PF6 -

33

N Mes

sIMes

O

biphasic with toluene (25:75, [bmim][PF6] : toluene)

15 November 2006

Ionic Liquids

Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J-C. J. Am. Chem. Soc., 2003, 125, 9248-9249.

AMA 33

The Future • Chiral functionalized ionic liquid – Side chain or anion incorporates chirality – Asymmetric induction – Kinetic resolution

• Task-specific ionic liquids – Incorporate reagent or catalyst or substrate into cation or anion – If substrate – can carry substrate on several steps, immobilized in ionic liquid – allows for easy separation/recovery

• Supercritical CO2

– Used to extract product from ionic liquid phase without using “molecular solvents”

15 November 2006

Ionic Liquids

AMA 34

Summary • Ionic liquids viable alternative to molecular solvents in many reaction types • Ionic liquids allow for potential recovery/reuse of catalyst (it may be the catalyst itself) • Rate enhancement, ease of product isolation, recyclability of catalyst – ionic liquids could become widely popular in near future

15 November 2006

Ionic Liquids

AMA 35

References • Properties: – Handy, S. T. Current Organic Chemistry, 2005, 9, 959-988. – Dupont, J.; Spencer, J. Angew. Chem. Int. Ed., 2004, 43, 5296-5297. – Baudequin, C.; Brégeon, D.; Levillain, J.; Guillen, F.; Plaquevent, J-C.; Gaumont, A-C. Tetrahedron: Asymmetry, 2005, 16, 3921-3945. (Chiral ionic liquids) – Welton, T. Chem. Rev., 1999, 99, 2071-2083.

• Reactions: – Sheldon, R. Chem. Commun., 2001, 2399-2407. – Song, C. E. Chem. Commun., 2004, 1033-1043. – Lee, S. Chem. Commun., 2006, 1049-1063. (Functionalized ionic liquids) – Miao, W.; Chan, T. H. Acc. Chem. Res., ASAP (Ionic liquidsupported synthesis) – Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetrahedron, 2005, 61, 1015-1060. 15 November 2006

Ionic Liquids

AMA 36