“If you’re going to take on a rule that’s been around for a hundred years, you have to have a certain type of mindset — being willing to go out on a limb.” — Neil Garg
By NAREN KRISHNA JEGAN — science@theaggie.org
In 1924, organic chemist Julius Bredt created an empirical observation about ringed molecules with a bonded carbon above or below the plane of the ring. He noted that an alkene (double-bonded carbon) cannot be placed at the bridgehead carbon (a carbon bonded to a sub planar or super planar branch with respect to the ring).
Dr. Jared Shaw, an organic chemistry professor at UC Davis, provided insight behind this observation.
“A double-bonded two-carbon molecule is flat,” Shaw said. “If each carbon atom has two substituents bonded to it, then those substituents will be in the same plane as the carbon. As you start to connect those atoms with rings, you introduce strain. A little bit of strain is okay, but if you have a double bond that’s at the bridgehead position […] then one of the rings has to be pretty big or there will be so much strain that the molecule will be very difficult — even impossible — to create.”
Researchers from the University of California, Los Angeles (UCLA) have found a way to create anti-Bredt olefins (ABOs), or molecules that systematically violate Bredt’s rule. While ABO research has been ongoing for multiple decades, this work provides a novel generalizable approach to synthesize ABOs that has a plethora of potential areas of future research.
Synthesizing ABOs is no easy task. UCLA graduate students Luca McDermott and Zach Walters, along with Professor Neil Garg, highlighted three main parts of the synthesis.
“People have performed ABO research in the past,” McDermott said. “All of them rely on some form of precursor you make. The ways a lot of people have done in the past to activate these precursors is very harsh; These methods allow you to generate ABOs but not in the presence of other functional groups.”
One major consideration of the precursors was stereochemistry, or the three-dimensional arrangement of atoms in a molecule.
“If you had the incorrect stereochemistry, the elimination reaction wouldn’t work at all,” McDermott said. “I remember heating our vessel higher and higher to see if it would react, but you wouldn’t get a reaction if you had the incorrect stereoisomer.”
Garg, Shaw and McDermott then explained one of the key mechanisms responsible for creating the ABOs the team was working on. In the context of precursors, McDermott introduced the Kobayashi method’s versatility with a variety of functional groups.
“The real beauty of the Kobayashi method is that you put the two substituents where you want the bond to form,” Garg said. “One side you put a silicon, the other a triflate or halide.”
The Kobayashi mechanism uses a fluoride source to attack the silyl group. Shaw points out that trimethylsilyl (TMS) contains silicon and, when near fluoride, will create a very strong interaction. This results in a simultaneous elimination reaction that results in the formation of a TMS–F complex, a triflate anion, and the strained bond between the locations of the original triflate and TMS groups. Using this principle, the team created a precursor compound with a silyl group and nonaflate, chloride or bromide leaving group at the location of the carbons where the double bond would exist. Adding a fluoride source, the TMS-F complex and the leaving group anion would be freed, resulting in the formation of an ABO with the desired location of the alkene.
Walters discussed how the team was able to contain such an unstable molecule. He rationaled that ABOs can react not only with other molecules, but even with themselves. In order to verify the presence of an ABO, they would need to trap it with something else, another reactant, such as anthracene.
“A big challenge that we encountered with strained compound chemistry was generating the compound slowly and using an excess amount of reactants to ensure proper synthesis,” Walters said.
One of the strategies used was pairing caesium fluoride (CsF) with tetra-butyl ammonium bromide, which was expected to undergo a double displacement reaction which would slowly release the fluoride ion in toluene to generate the ABO in small amounts.
“The key there was using toluene […] We saw poor reactivity in other solvents at elevated temperatures,” Walters said. “Using the tetra-butyl ammonium bromide meant that having a solvent where CsF would be insoluble was very important.”
Using this approach, the team was able to create eight types of ABOs, confirmed by analysis of trapping reactions using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, the team was able to show that the ABOs were chiral, showcasing the ability to design stable yet highly strained molecules with well-defined stereochemistry, expanding the field’s understanding of molecular stability and reactivity.
“There are a few scattered examples of people making ABO’s over the last few decades […] so it’s not shown to be impossible,” Garg said. “The purpose of our paper is […] to show that you can make ABO’s in a general way; and that’s what now makes it really possible. It shouldn’t be lost upon anybody the amount of work and creativity from the students and postdocs that went into this is enormous […] This [work] is the result of four PhD students, two postdocs and our UCLA collaborator Professor Ken Houk.”
Research on this topic will continue for years to come, and the results of this study will be an avenue for future discoveries and scientific progress. For more information about this work and the members who contributed, check out the original study and the Garg Lab’s website.
Original Article:
Luca McDermott et al., A solution to the anti-Bredt olefin synthesis problem.
Science386,eadq3519(2024).DOI:10.1126/science.adq3519
Contributing Authors:
Luca McDermott, Zach Walters, Sarah French, Allison Clark, Jiaming Ding, Andrew Kelleghan, K.N. Houk, Neil Garg
More Information About the Garg Research Group:
Written by: Naren Krishna Jegan — science@theaggie.org