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 contact-fti@fluorous.com. 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.