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Organic Synthesis
Adam M. Azman
15 November 2006
15 November 2006
Ionic Liquids
AMA 1
15 November 2006
Ionic Liquids
AMA 2
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)
AlCl3
N Cl
R
H
Et 3 NHCuCl2
N
PF6
15 November 2006
Ionic Liquids
AMA 3
15 November 2006
Ionic Liquids
AMA 4
(very)
AlCl3
N
Cl-
Large, asymmetric anions should lower melting point, as should large, asymmetric cations
R N
N R
Al2 Cl7 -
It was noticed that large anions with many degrees of freedom inhibited
crystalization until lower temperature
R
H
Start of modern era of ionic liquids began with discovery of 1butylpyridinium chloride-aluminum chloride mixture
Early 1990s Ethylmethylimidazolium halides prepared, then anion metathesis with various silver
salts provided a small library of room temperature ionic liquids
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
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
Conductivity
Ionic Liquids
AMA 7
The Cation
Infinite in number
Most common:
Dialkylimidazolium N N
N R
Alkylpyridinium
R
Tetraalkylammonium R N R R
R
Tetraalkylphosphonium R PR R
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 S
O
O
F
F
OO
O
S
F
N
F F
F
O S
O
O F
-
O S
F
O F
15 November 2006
Ionic Liquids
AMA 9
Br
Cl
250
Me N
Ms
NTf2
200
PF6
Melting Point (deg C)
N R
X-
Tf
150
100
50
0
0
10
12
14
16
18
20
-50
-100
Le ngth of Alkyl Cha in (# Ca rbon Atom s)
80
R N
N R
PF6 -
symmetrically substituted
imidazolium cation
[RRim][PF6 ]
15 November 2006
Ionic Liquids
60
40
20
0
-20 0
-40
-60
-80
-100
# Carbon atoms (per side)
AMA 10
10
15 November 2006
Ionic Liquids
AMA 11
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?
15 November 2006
Ionic Liquids
AMA 14
Limitations
15 November 2006
Ionic Liquids
AMA 15
Applications
Wittig
Hydroformylation
Robinson annulation
Alkoxycarbonylation
Dihydroxylation
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
Cyanosilyation of aldehydes
Synthesis of 3,4-dihydropyrimidin-2(1H)ones
Esterification
Dimer-/Oligomer-/Polymerization
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-]
R2
O O
No added catalyst
1:1 ratio of carbonyl to diol
No refluxing/Dean-Stark trap
No molecular solvent
Recyclable catalyst
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
HO
OH
1:1
100
98
HO
OH
1:1
3 .5
100
100
HO
OH
1:1
100
93
HO
OH
1:1
100
76
1:1
100
93
1:1
100
100
OH
1:1
100
97
OH
1:1
100
94
OH
1:1
100
OH
1:2
100
100
OH
1:2
100
60
OH
1:2
100
100
O
O
O
O
Ph
H
O
H
HO
OH
HO
OH
HN
BF 4 -
[Hm im ][BF 4 ]
NO 2
O
nh e x
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 Bu
X-
[bbim][X]
HN
N Bu
X-
[Hbim][X]
R3
Ionic Liquid
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
NH 2
NH 2
O
Me
H
O
N
H
N
N
H
N
H
O
N
O
Ar
15 November 2006
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,
R2
A
B
N H2
R 2 =Me
R 2 =Ph
O
OE t
N
R2
Me
O
OE t
R1
Me
Me
A
B
R2
R1
Me
[H b im ][BF 4 ]
Pro d u ct
O
R1
R2
R3
Me
N
Tim e (h )
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
A 96 96
B 98 96
94
96
A 97 96
B 97 95
95
95
A 94 94
B 93 92
93
91
N
R2
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
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 (% )
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
EWG
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 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
CN
EWG
gl yci n e (0 .2 e q .)
E WG
CN
O
Cl
86
CN
CN
CN
O 2N
CN
77
CN
CN
CN
O
M eO
OH
74
H
NC
CN
O 2N
CN
PF 6-
g ly cin e
H
NC
n h ex
H 2N
H
NC
[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
32
CN
O
O
EtO
15 November 2006
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
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)
99
6 9 (R )
99
7 2 (R )
99
7 7 (R )
99
7 0 (R )
100
78 (S)
100
84 (S)
90
79 (S)
95
67 (S)
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
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
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
DielsAlder
O
S c(OTf )3 ( 0.2 mo l% )
s ol ve n t, rt, 2 h
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
Y ie ld (% )
>99 :1
94
[bmim][PF6 ]
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
N Bu
PF6 -
Me N
15 November 2006
En d o :ex 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
H
N
N
Mn
t-Bu
O
t-Bu
Cl
t-Bu
t-Bu
(R,R)-Jacobsen's Catalyst
15 November 2006
Ionic Liquids
AMA 26
Olefin Epoxidation
R1
R3
R2
R4
Substrate
Product
O
R1
R2
R3
R4
Me N
Time (h)
Yield (%)
% ee
86
73 73 60 53
96
90 90 89 88
72
94
N Bu
PF6 -
[bmim][PF 6]
O
O
O
NC
NC
O
4
72
Ph
84
t-Bu
O
Me
N
Mn
t-Bu
Ph
H
N
Cl
t-Bu
t-Bu
(R,R)-Jacobsen's Catalyst
Me
3
72
86
77
84
O
O
15 November 2006
Ionic Liquids
Song, C. E.; Roh, E. J. Chem. Commun., 2000, 837-838.
AMA 27
Heck Reaction
Ph
Br
Pd
Pd P
P
I
BuO
N
N
Me
IPh
OBu
P
Pd P
Ph
Ph
OBu
Pd P
OBu
Ph
BuO
Ph Pd P
P
Pd P
Ph
Ph
OBu
Bu
OBu
Bu
N
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
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
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
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
9 4%
6 s te p s
no ch ro ma to gr ap y
TfO -
- 78 C
O
15 November 2006
(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
(COCl)2 , NEt3
CH 2Cl2/MeCN
TfO -
O
S
N
TfO -
-78 C
O
OH
Substrate
Product
OH
Yield(%)
O
90
OH
OH
81
88
95
H
OH
86
BnO
87
BnO
O
82
O
Me Me
O
Me Me
Me
Me
90
OH
15 November 2006
Ionic Liquids
He, X.; Chan, T. H. Tetrahedron, 2006,62, 3389-3394
AMA 31
RCM
HO
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
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
PF6-
N
N
O
R
[bmim][PF6 ], 60 C
! 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
>98
>98
>98
96
93
91
80
>98
>98
>98
>98
>98
>98
95
[bmim][PF6 ]
95
Mes N
EtO 2C CO2 Et
EtO2 C CO 2Et
sIMes (25C)a
O
PCy3
>98
>98
>98
94
78
48
>98
>98
>98
83
PF6 -
33
N Mes
sIMes
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
Supercritical CO2
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.; Brgeon, 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