Fluorous chemistry lecture slides courtesy of

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advanced separation

chemistry for

life sciences

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 separation.

and the fluorinated domain controls The aim is to facilitate separation.

Development of fluorous chemistry

1991 Thesis by Vogt (Univ. of Aachen) on the use of perfluorinated ethers to immobilize homogeneous catalysts 1993 Zhu (3M) reported on azeotropic separations using perfluorocarbon solvents 1994 1999 Seminal paper by Horv áth & Rabai (ExxonMobil) in

Science

described the use of heavily-fluorinated compounds in fluorous solvents for hydroformylation: biphasic catalysis. Term “fluorous” is introduced.

Curran (Univ. of Pittsburgh) develops “light” fluorous chemistry. The less-fluorinated compounds were soluable in organic and hybrid solvents, making fluorous techniques more practical in organic synthesis.

2000 2004 Fluorous Technologies, Inc. founded to commercialize light fluorous chemistry.

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 permanent fluorinated domains: Fluorous compounds with permanent fluorinated domains: 3 2 C 6 F 13 PPh 3 Ph 2 P C 6 F 13 Bu 3 SnH (C 6 F 13 CH 2 CH 2 ) 3 SnH Bu 3 SnH (C F CH CH ) SnH Fluorous compounds with temporary fluorinated domains (tags): Fluorous compounds with temporary fluorinated domains (tags): Ph Ph N O N O O H N OSi(CH) 3 OSi(CH) 3 CO 2 H Ph Ph N O O O Si O Si H N C 8 F 17 C 8 F 17 CO 2 H O O H N CO 2 H F 17 C 8 O O H N CO 2 H O Ph F 17 C 8 O Ph

“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 extraction

A 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.

organic aqueous fluorous

This can be exploited if a liquid-liquid separation is preferable, although reactivity is limited to the phase interface.

Light fluorous separation is an affinity technique

A

fluorous sorbent

is a chromatographic packing material modified with a

highly fluorinated domain

.

Si O Si F F F F F F F F F F F F F F F F F 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).

Solid-phase extraction

A light fluorous technique

fluorous dye O O N H N C 7 F 15 F 15 non-fluorous dye O O N H C N 4 C 4 H 9

1

O O NH 2 NH 2 O O N H N C 4 C 4 H 9 1. Load sample 2. Fluorophobic wash to remove organics: e.g. MeOH-H 2 O

(85:15)

3. Fluorophilic wash to elute fluorous species: e.g. THF 1. Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714.

2. Curran, D. P.

Synlett

. 2001, 9, 1488.

2 3

Fluorous HPLC

example: separaration by fluorine content

O

C n F 2n+1

N O N 80:20 MeOH: H 2 0

0 5 10 15 Minutes 20 25 30

100% MeOH

Fluorous-adapted organic synthesis

Chemical reaction compatibility

Ionic

Enolate, Grignard, lithiate, cationic

Free Radical

Cyclization, dehalogenation, deoxygenation

Lewis Acidic

Friedel-Crafts acylation, BBr 3

Transition metal catalyzed

Suzuki, Heck, Buchwald, Stille, Co, Rh

Reduction/oxidation

LAH, hydrogenation, H 2 O 2 , Swern

Applications in organic synthesis

The Mitsunobu Reaction

O 2 N CO 2 H NO 2

+

ROH

RfCH 2 CH 2 OCON=NCO 2 CH 2 CH 2 Rf PhP(

p

-C 6 H 4 CH 2 CH 2 Rf) 2 THF Ester + hydrazide + phosphine oxide

CO 2 R

organic

O 2 N NO 2

SPE fluorous

RfCH 2 CH 2 OCONHNHCO 2 CH 2 CH 2 Rf

+

PhP(O)(

p

-C 6 H 4 CH 2 CH 2 Rf) 2

S. Dandapani, (Fluorous Technologies); unpublished work

Comparative NMR’s

using combinations of organic & fluorous reagents

O 2 N NO 2 Ph 3 PO CO 2 Me

Prod TTPO

EtO 2 CNHNHCO 2 Et

DEH TTPO Prod Prod DEH DEH

10 8

Slide courtesy Prof. D. P. Curran

6 4 2 0

Fluorous scavenging

a solution-phase fluorous application

Curran, D., Zhang, w., et al., Tetrahedron, 2002, 58, 3871

Biopolymer purification

an emerging fluorous application

Add fluorous tag

Capped deletion sequence

Detag, then SPE

MeOH

Cleave from resin, deprotect side chains, then SPE

MeOH + H 2 O

Clean product Tagged product

Overkleeft, H.S., et al. Tetrahedron Letters 2003, 44, 9013-9016

Unwanted organics

Fluorous biphasic catalysis

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.

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 biphasic catalysis

O hexane + R 3 SiH warm O + R 3 SiH C 6 F 11 CF 3 F 3 HRhL F 3 L F = P(CH 2 CH 2 C 6 F 13 ) 3 or P(CH 2 CH 2 C 8 F 17 ) 3 react cool OSiR 3 + OSiR 3 separate phases HRhL F 3 HRhL F 3 + OSiR 3 + OSiR 3 Hydroformylation with a fluorous Wilkinson's catalyst 1. T. Horvath, J. Rabai, Science 1994 ,

266

, 72-75.

2. Horvath, I. T. Acc. Chem. Res. 1998, 31, 641.

Fluorous triphasic separation

Chiral separation of 2-Napthylethanol

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.

One of the two enantiomers (which are intermixed) is fluorous tagged F 17 C 8 O O + OH (R)-

15

OH (S)-

15

OH (R)-

15

(S)-

14 Source phase

Only the (S) enantiomer is soluble in the fluorous phase; it migrates while (R) stays behind MeOH

Receiving phase

MeO MeOH FC-72

Fluorous phase

days Curran, D. P. et al.

Organic Letters

2002, 4, 15, 2585-2587.

(R) F 17 C 8 CO 2 Me (S)