Volume 87 Issue 41 | pp. 45-49
Issue Date: October 12, 2009

Fluorine With A Flourish

Rocky Mountains provide a unique venue for a joint conference on a unique element
Department: Science & Technology
Keywords: fluorine, fluorous, noble gas, oligosaccharide
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“Our goal was to provide fluorine chemists with a place they could come to and get renewed and go away with fresh research ideas and a lot of memories.”
Credit: Steve Ritter/C&EN
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“Our goal was to provide fluorine chemists with a place they could come to and get renewed and go away with fresh research ideas and a lot of memories.”
Credit: Steve Ritter/C&EN

Fluorine holds a special place in the hearts of many chemists. Because of its unique reactivity and the many laudable qualities it brings to chemical compounds, fluorine is one of the only elements that chemists broadly study on an exclusive basis. As a result of that focus, fluorine chemists belong to a close-knit community of researchers and rally for specialty conferences.

The most recent of these gatherings, the combined 19th International Symposium on Fluorine Chemistry and 3rd International Symposium on Fluorous Technologies (ISoFT), was held in late August in Grand Teton National Park, in Wyoming. The backdrop of the mesmerizing Grand Teton mountain range and the possibility of spotting wildlife at any moment, coupled with cultural and social events packed in with the technical sessions, provided a unique experience for fluorine aficionados.

“With the scenery and good science, our goal was to provide fluorine chemists with a place they could come to and get renewed and go away with fresh research ideas and a lot of memories,” conference organizing committee chair Joseph S. Thrasher of the University of Alabama told C&EN.

One of the meeting highlights was a plenary session honoring Herbert W. Roesky of the University of Göttingen, in Germany, as recipient of the 2009 Moissan International Prize. This honor is a lifetime achievement award in fluorine chemistry presented every three years by France’s Maison de la Chimie. The award is named for Frenchman Henri Moissan, who first isolated fluorine in 1886.

Roesky described his career research on organometallic fluorides and main-group and metal cluster compounds. He also revealed details of his latest work on rare silicon(II) compounds, which he and his collaborators prepared by stabilizing silicon with N-heterocyclic carbenes. Roesky showed that these compounds react with diphenylacetylene to form trisilacyclopentenes—five-membered heterocyclic rings containing two carbon and three silicon atoms. “This type of reactivity opens up a new direction in chemistry for silicon(II) compounds,” Roesky said.

While the conference attendees celebrated Roesky’s accomplishments, they also remembered two of their colleagues who died in 2008. Memorial symposia were held in tribute to Neil Bartlett of the University of California, Berkeley, a leading inorganic chemist, and J. Colin Tatlow of the University of Birmingham, in England, a leader in developing synthetic routes to aromatic fluorine compounds.

Bartlett’s research in particular has become part of chemistry lore. At the University of British Columbia in 1962, Bartlett synthesized the first known noble-gas compound, XePtF6. His discovery shattered the common belief that noble gases were inert and couldn’t be induced to react with other chemical species to form covalent bonds.

Nowadays, an array of noble-gas compounds are known, including Xe2Au2F3+ and Xe3OF3 + salts; KrF2, RnF2, and salts derived from them; and a lone argon compound, HArF. In one of the latest creations, Hermann-Josef Frohn and coworkers of the University of Duisburg-Essen, in Germany, announced at the conference the first example of a zwitterionic noble-gas compound.

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Zwitterions are neutral molecules that have nonadjacent atoms bearing formal positive and negative charges; amino acids under physiological conditions are a primary example. In Frohn’s case, his team had been investigating fluorine substitution in XeF2 by nucleophilic carbon compounds, Frohn said, with a goal of synthesizing para-substituted dixenonium species, such as (Xe+)C6F4(Xe+). When the researchers reacted XeF2 with the highly acidic borane (BF2)2C6F4, they discovered the zwitterion (Xe+)C6F4(BF3 ) as the major product. The isolated zwitterion is surprisingly stable at room temperature in acetonitrile solvent and decomposes on heating at 148 °C, Frohn reported.

The type of research carried out by Roesky, Bartlett, and Frohn is becoming endangered. As Bartlett told C&EN in a 2002 interview: “Who is interested in this sort of exotica these days? The funding agencies want to have assurance that there’s some practical outcome. And frankly, that’s deadening for this kind of research because one can’t easily foresee the benefits.”

Several of the attendees echoed that sentiment in remembering Bartlett, because many senior fluorine chemists built their careers out of such pie-in-the-sky research. Jack Passmore of the University of New Brunswick, a Bartlett graduate student in the 1960s, noted two concepts that Bartlett taught him and that he continues to follow: “Create simple compounds of interest in terms of bonding and stereochemistry, and try to do it in one simple step to make synthetically useful quantities.”

SAFER AND VERSATILE
Fluolead is a stable crystalline fluorinating reagent with an improved safety profile and more versatility in preparing fluorinated compounds.
Credit: Teruo Umemoto
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SAFER AND VERSATILE
Fluolead is a stable crystalline fluorinating reagent with an improved safety profile and more versatility in preparing fluorinated compounds.
Credit: Teruo Umemoto

In Wyoming, Passmore described his long-term studies of inorganic sulfur chemistry, including recent work on deciphering the complex bonding in sulfur-iodine salts, such as [S2I42+][AsF6 ]. Bartlett’s philosophy “really drives the desire to keep after a problem until it can be understood,” Passmore told C&EN. “That understanding is what provides a basis of knowledge that allows building up to practical applications.”

Two areas emphasized at the conference that have benefited from that thinking and where applied fluorine chemistry is flourishing are the design and synthesis of new active pharmaceutical ingredients and fluorous technologies for the synthesis and separation of biomolecules.

Although fluorine imparts enhanced biological activity to drug molecules or desirable changes in physical properties to improve drug delivery, organofluorine chemistry confronts chemists with a daunting challenge: selectively synthesizing fluorine compounds by design is difficult to do. One approach is to start with a fluorine-containing building block, while another approach is to introduce fluorine at an appropriate stage during synthesis. The decision on which way to begin depends on whether or not having the fluorine in place will hinder later steps in a synthesis and the cost of purchasing a fluorinated starting material versus do-it-yourself fluorination.

Either way, chemists need practical fluorinating reagents. In the early years of fluorine chemistry, researchers often used highly reactive elemental fluorine gas diluted in nitrogen, toxic sulfur tetrafluoride gas, and corrosive anhydrous hydrogen fluoride. These brute-force reagents typically require specialized reaction vessels on vacuum line systems and specialized training. For many fluorine chemists, a goal became to develop fluorinating reagents and procedures that can be run on the benchtop without any special needs.

A number of these easily handled reagents and methods have emerged and offer a kinder, gentler approach that is revolutionizing fluorine chemistry. In the latest example, Teruo Umemoto, president of IM&T Research, in Denver, reported a new reagent called Fluolead, or 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride.

Fluolead is an alternative to diethylaminosulfur tri­fluoride (DAST), which itself is a popular alternative to SF4 for deoxofluorination reactions of alcohols, aldehydes, and ketones to make –CH2F, –CHF2, and –CF2– groups, respectively. As a liquid, DAST is easier to handle than SF4, but it’s still thermally sensitive and isn’t safe to handle above 50 °C, Umemoto noted. It also has the shortcoming of fuming in air and reacting vigorously with water.

“DAST has long been a useful reagent with wide application,” Umemoto said. “However, its relatively unstable and potentially explosive nature precludes significant application in large-scale industrial processes.”

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Fluolead is a crystalline solid that doesn’t fume in air, doesn’t immediately react with water, and can be safely handled at up to 150 °C, Umemoto noted. IM&T’s synthesis, which can be run on a kilogram scale, begins by preparing an aryl disulfide (ArSSAr) and then converting it to Fluolead by reaction with Cl2 and KF. Fluolead’s capabilites go beyond those of DAST and its analogs, Umemoto said, as it can convert carboxylic acids to –CF3 groups and easily convert nonenolizable ketones to –CF2– groups.

The pharmaceutical industry “should lap it up,” said Graham Sandford of the University of Durham, in England, when asked about Fluolead’s potential. “A fluorinating reagent that is a shelf-stable solid, doesn’t fume, can be handled safely without any special precautions, and improves on existing reagents could be very useful indeed for drug discovery,” Sandford told C&EN.

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Rxn Scheme
In a fluorous phase-vanishing reaction, a fluorinated solvent serves as a screen to separate some of the reactants. As one reactant diffuses through the fluorous phase, the reaction--in this case a Friedel-Crafts acylation--takes place. The technique is a general method for controlled organic synthesis.
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Rxn Scheme
In a fluorous phase-vanishing reaction, a fluorinated solvent serves as a screen to separate some of the reactants. As one reactant diffuses through the fluorous phase, the reaction--in this case a Friedel-Crafts acylation--takes place. The technique is a general method for controlled organic synthesis.

Umemoto’s presentation on Fluolead drew wide attention, but he wasn’t done with making new announcements. In a separate presentation, Umemoto described an improved synthesis of arylsulfur pentafluorides (ArSF5) that came about while developing Fluolead.

The SF5 group on an aromatic ring is more lipophilic and electronegative than a CF3 group—making it an even more attractive functional group in pharmaceutical and agrochemical arenas than CF3. In fact, SF5 has been labeled the “substituent of the future” by prominent organofluorine chemists. The problem is there isn’t a sufficient large-scale synthesis of SF5 compounds.

Umemoto and colleagues observed formation of a minor product during the fluorination step to make Fluolead that turned out to be ArSF4Cl. With extended work, the researchers perfected a large-scale synthesis of a range of ArSF4Cl compounds. Ume­moto subsequently found that the SF4Cl group could readily be converted to SF5 in a solventless reaction with ZnF2.

Both Fluolead and the ArSF5 synthesis have been patented and are in the hands of IM&T’s licensing partner, Japan’s Ube Industries, which is pursuing commodity-scale production of the compounds, Ume­moto told C&EN.

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Team
Beatrice Collet of Lucella BioSciences, holding a fluorous microarray slide, with Xueshu Li (left) and Eun-Ho Song (right) of Iowa State next to a printer used to prepare oligosaccharide microarrays.
Credit: Shu-Lun Tang
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Team
Beatrice Collet of Lucella BioSciences, holding a fluorous microarray slide, with Xueshu Li (left) and Eun-Ho Song (right) of Iowa State next to a printer used to prepare oligosaccharide microarrays.
Credit: Shu-Lun Tang

The SF5 synthesis “is a sweet reaction,” noted John T. Welch of the State University of New York, Albany, who has conducted side-by-side comparisons of SF5 and CF3 analogs of herbicides and drug compounds. Now that a high-yield synthesis seems to be worked out, “SF5 stands to make a big impact for applications of pharmaceutical and agricultural chemicals,” Welch said.

A highlight of the fluorous portion of the conference was the presentation of the 2009 ISoFT Award to Ilhyong Ryu of Osaka Prefecture University, in Japan, in recognition of his efforts to create novel fluorous “phase-vanishing reactions.”

Fluorous-phase chemistry, named by analogy with the aqueous phase, takes advantage of the preference fluorinated compounds have for one another over organic compounds and water. In Ryu’s phase-vanishing reactions, a fluorinated solvent acts as a screen to initially separate a reactant from the target substrate in a hydrocarbon solvent—a triphasic system. Over time, the reagent, which is partially soluble in the fluorinated solvent, migrates through the fluorous phase to come in contact with the substrate, where the reaction occurs, Ryu explained. The reagent phase disappears once it migrates completely to the substrate phase—hence the term “phase vanishing.” The product is isolated from the organic layer.

Ryu provided several examples of phase-vanishing reactions, including bromination of alkenes by Br2 and Friedel-Crafts acylation of aromatic compounds using SnCl4 as a catalyst. Ryu’s latest result is a Barbier reaction in which CH3I is placed in the bottom of a reaction tube, followed by perfluoro­polyether solvent, magnesium turnings, and then an organic solvent containing a ketone. As CH3I migrates up through the fluorous layer, it forms a Grignard reagent with magnesium that subsequently converts the ketone to an alcohol. Diffusion of the reagent through the fluorous phase helps control the speed of the reaction and thereby allows for controlling the heat generated, Ryu noted.

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Conclave
Attendees of 19th International Symposium on Fluorine Chemistry and 3rd International Symposium on Fluorous Technologies assemble before a backdrop of the Grand Teton Mountain Range.
Credit: Steven Strauss
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Conclave
Attendees of 19th International Symposium on Fluorine Chemistry and 3rd International Symposium on Fluorous Technologies assemble before a backdrop of the Grand Teton Mountain Range.
Credit: Steven Strauss

Another way in which scientists take advantage of fluorous properties is by using long-chain fluorocarbons as tags to shepherd reagents or substrates through a reaction sequence and separation. The versatile tagging strategy has been adapted for small-molecule chemical library synthesis, synthesis and purification of peptides and nucleic acids, and microarray assays of biomolecules.

The hot topic for now though is carbohydrates, and several scientists at the conference discussed their efforts to improve mono- and oligosaccharide synthesis. Oligosaccharides, also known as glycans, are polymeric sugars that play key roles in biochemistry, including attaching to proteins to aid in protein folding and sitting on the surface of cell membranes to mediate cellular recognition. But unlike the synthesis of peptides and nucleic acids, automated solid-phase methods in which the biomolecules are covalently bound to solid beads during synthesis and purification steps haven’t worked well for oligosaccharides.

That’s where fluorous chemistry proves its worth, said Nicola L. B. Pohl of Iowa State University, who gave a keynote lecture describing her group’s adventures in developing automated solution-phase oligosaccharide synthesis technology made possible by noncovalent fluorocarbon interactions. Her team typically takes advantage of a C8 perfluorinated ether attached to a sugar group to purify synthetic intermediates and guide them to the next reaction step.

All the reactions are carried out in solution in an automated synthesizer, Pohl explained, but the intermediates and final products are isolated by fluorous solid-phase extraction in which the fluorous-tagged saccharide is immobilized by noncovalent interactions on a fluorine-modified silica cartridge while unwanted reagents are washed away. The fluorous-tagged saccharide is subsequently eluted off. This sequence can be repeated as many times as needed to lengthen the saccharide chain.

For solid-phase synthesis, oligosaccharides require large excesses of costly building blocks to drive reactions to completion, Pohl noted. Add in the multiple protection-deprotection and derivitization steps and it makes solid-phase synthesis impractical. “It’s a daunting task to detect each sugar as it’s added and ensure the linkages are appropriate and that the stereochemistry is correct,” Pohl said. “The fluorous solution-phase method simplifies the process to solve those problems and ensures reproducibility, which is important if you need to synthesize more of an oligosaccharide when it turns out to be biochemically interesting.”

As a bonus, the fluorous tags have a strong affinity for the surface of glass slides coated with a fluoroalkylsilane. Thus, the as-synthesized oligosaccharides can be directly spotted on the surface of a slide to form a microarray and then exposed to an enzyme or antibody labeled with a fluorescent dye to find binding partners.

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Working with the university, Pohl has just started a company, LuCella Biosciences, to fulfill the unmet need of offering custom carbohydrates made via the automated fluorous system. Pohl also has been collaborating with Pittsburgh-based company Fluorous Technologies since 2005 via a National Institutes of Health grant to develop new applications for the fluorous microarray slides her team developed. Fluorous Technologies is already selling the slides for lab preparation of peptide, oligonucleotide, and oligosaccharide microarrays.

“Fluorine chemistry has come a long way since the accidental discovery of polytetrafluoroethylene in the 1930s,” observed Cynthia C. Green, president of DuPont Fluoroproducts, who made remarks at a banquet on the final evening of the conference. There have been many innovations in fluorine science since then that have societal value, she said, some of them made by chemists in the banquet hall. But the time is ripe for a new age of fluorine chemistry, she suggested.

Trends in global population growth indicate that the world will soon have a much larger middle class with expectations of having a higher standard of living, Green noted. That possibility is driving R&D investments in fluorine chemistry to ensure that new products—from solar cells and batteries to insulation and refrigerants—are available for future markets. “The challenge for us, as fluorine chemists, is to meet those needs in a sustainable and affordable way,” Green concluded.

 
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