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advanced separationchemistry forlife sciences
Fluorous chemistry lecture slides courtesy of
These slides are provided to the academic community in the interest of promoting scientific awareness of this new area of chemistry. They may be freely used and adapted for instructional purposes. FTI encourages you to forward them to colleagues. Please include this informational cover slide when forwarding. These slides and their components may not be used in commercial activities or in publications without prior permission from FTI. Research attributions, where they appear, must always accompany individual slides. Background graphics and other decorative clutter are omitted in case you want to apply your own graphic standards. Notes are attached to each slide.
We appreciate (but do not require) acknowledgement when these slides are used. For more information, questions or comments, contact FTI at 412-826-3050 or [email protected]. Additional slides with fluorous reaction examples are also available.
Protein structure courtesy Protein Data Bank, PDB ID 152L, J.Zhang,B.Matthews
Introduction to fluorous chemistry
Fluorous molecules comprise an organic domain and a highly fluorinated domain. Ideally, the organic domain controls reactivity and the fluorinated domain controls separation. The aim is to facilitate separation.
Development of fluorous chemistry1991 Thesis by Vogt (Univ. of Aachen) on the use of
perfluorinated ethers to immobilize homogeneous catalysts
1993 Zhu (3M) reported on azeotropic separations usingperfluorocarbon solvents
1994 Seminal paper by Horváth & Rabai (ExxonMobil) in Science
described the use of heavily-fluorinated compounds influorous solvents for hydroformylation: biphasic catalysis. Term “fluorous” is introduced.
1999 Curran (Univ. of Pittsburgh) develops “light” fluorous
chemistry. The less-fluorinated compounds were soluablein organic and hybrid solvents, making fluorous techniquesmore practical in organic synthesis.
2000 Fluorous Technologies, Inc. founded to commercialize
light fluorous chemistry. 2004 Peters et al (GNF/Novartis) report use of fluorous tags
for protein enrichment in proteomics applications.
Two basic approaches
Fluorous compounds with integral (permanent) fluorinated domains:
Fluorous compounds with removable (temporary) fluorinated domains (tags):
“Heavy” versus “light”
Generally, > 60% fluorine by weight is called a “heavy fluorous” compound. These materials have limited solubility in non-fluorous media, typically require perfluorinated solvents, and are expensive - all of which limits practical adoption.
“Light fluorous” compounds (< 40% by weight) are miscible in organic solvents and cost less. Since they typically will not form a separate fluorous liquid phase, light fluorous compounds are separated using a companion fluorous stationary phase.
Liquid-liquid extractionA heavy fluorous technique
Whereas compounds bearing light fluorous tags are miscible in organic solvents, heavy fluorous compounds are soluble in perfluorinated solvents and form a distinct liquid phase.
This can be exploited if a liquid-liquid separation is preferable, although reactivity is limited to the phase interface.
organic
aqueous
fluorous
Light fluorous separation is an affinity technique
A fluorous sorbent is a chromatographic packing material modified with a highly fluorinated domain.
Fluorous stationary phases exhibit high selectivity for retention of fluorous versus non-fluorous molecules. In addition, fluorous sorbents are able to resolve fluorous molecules of differing fluorine content (e.g. different size or number of fluorous tags).
Si O SiF
F F
F F
F F
F F
F F
F F
F F
F F
1. Load sample
2. Fluorophobic wash to remove organics: e.g. MeOH-H2O (85:15)
3. Fluorophilic wash to elute fluorous species: e.g. THF
fluorous dye non-fluorous dye
Solid-phase extraction
1 2 3
A light fluorous technique
1. Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714.2. Curran, D. P. Synlett. 2001, 9, 1488.
Fluorous HPLCexample: separaration by fluorine content
0 5 10 15 20 25 30
C 7H 15
C 3F 7
C 4F 9
C 5F 11
C 6F 13
C 8F 17C 7
F 15
C 9F 19
C 10F 21
80:20MeOH:
H20
100%MeOH
Minutes
CnF2n+1
Fluorous-adapted organic synthesis
IonicEnolate, Grignard, lithiate, cationic
Free RadicalCyclization, dehalogenation, deoxygenation
Lewis AcidicFriedel-Crafts acylation, BBr3
Transition metal catalyzedSuzuki, Heck, Buchwald, Stille, Co, Rh
Reduction/oxidationLAH, hydrogenation, H2O2, Swern
Chemical reaction compatibility
Applications in organic synthesisThe Mitsunobu Reaction
CO2H
O2N NO2
+ ROHRfCH2CH2OCON=NCO2CH2CH2Rf
PhP(p-C6H4CH2CH2Rf)2THF
Ester
+
hydrazide
+
phosphine oxide
organic
fluorous
CO2R
O2N NO2
RfCH2CH2OCONHNHCO2CH2CH2Rf+
PhP(O)(p-C6H4CH2CH2Rf)2
SPE
S. Dandapani, (Fluorous Technologies); unpublished work
Comparative NMR’susing combinations of organic & fluorous reagents
0246810
O2N
NO2
CO2Me
Ph3PO
EtO2CNHNHCO2Et
Prod
TTPO
DEH
Prod
Prod
TTPO
DEH
DEH
TTP + DEADTTP + FDEADFTTP + DEADFTTP + FDEAD
Slide courtesy Prof. D. P. Curran
Fluorous scavenginga solution-phase fluorous application
Curran, D., Zhang, w., et al., Tetrahedron, 2002, 58, 3871
Biopolymer purificationan emerging fluorous application
MeOH
MeOH+
H2O
Overkleeft, H.S., et al. Tetrahedron Letters 2003, 44, 9013-9016
Addfluorous
tag
Cleavefrom resin,deprotect
side chains,then SPE
Clean product
Unwanted organics
Tagged product
Capped deletion
sequence
Detag,then SPE
Fluorous biphasic catalysis
1. T. Horvath, J. Rabai, Science 1994, 266, 72-75.2. Olofsson, K.; Kim, S. Y.; Larhed, M.; Curran, D. P.; Hallberg, A., J. Org. Chem. 1999, 64, 4539-4541.
Fluorous-tagged ligands enable reliable L-L separation of catalyst – important for toxic and/or expensive catalysts. Variation shown here is thermomorphic fluorous biphasic catalysis. Solubility of the fluorous species in organic phase is promoted with heat, improving kinetics.
hexane
C6F11CF3
O
+ R3SiH
1% ClRhLF3
O
HRhLF3
+ R3SiHwarm react
cool
OSiR3 OSiR3
HRhLF3
+
+
HRhLF3
OSiR3 OSiR3
+
separate
phases
LF = P(CH2CH2C6F13)3 or P(CH2CH2C8F17)3
1. T. Horvath, J. Rabai, Science 1994, 266, 72-75.2. Horvath, I. T. Acc. Chem. Res. 1998, 31, 641.
Hydroformylation with a fluorous Wilkinson's catalyst
Fluorous biphasic catalysis
OHO
O
F17C8
OH OH
F17C8
CO2MeFC-72
MeOH MeO-
MeOH
days
+
(R) (S)
(S)-14 (R)-15
(R)-15 (S)-15
Fluorous triphasic separation
One of the two enantiomers (which are intermixed) is fluorous-tagged
Only the (S) enantiomer is soluble in the fluorous phase; it migrates while (R) stays behind
The receiving phase contains a reagent to remove the fluorous tag, leaving a clean (S) product. The tag itself prefers to be in the fluorous phase and migrates back there, where it accumulates.
Sourcephase
Receivingphase
Fluorous phase
Chiral separation of 2-Napthylethanol
Curran, D. P. et al. Organic Letters 2002, 4, 15, 2585-2587.