A reagent that can selectively transform carbon-hydrogen bonds is something organic chemists have been seeking for more than 25 years. Organic chemist John Hartwig and colleagues at the University of California, Berkeley, have now discovered a catalyst that can functionalize the strongest C–H bond on an alkane (Science 2020, DOI: 10.1126/science.aba6146). Unlike past C–H functionalization reactions, this one marches forth without a directing group and without the need for large amounts of substrate to move quickly, allowing the researchers to modify more complex molecules than before.
In C–H functionalization reactions, reagents tend to attack the weakest and most electron-rich carbon bond in a molecule, or the bond that chemists point to by installing directing groups. This new reaction overcomes those previous limitations and attacks primary C–H bonds over secondary ones and at carbons two atoms away from the heteroatom in saturated alkyl rings.
Every other known C–H activation method attacks either at the atom next to the heteroatom or as far away as possible from the heteroatom, Hartwig says. With the new catalyst, “we can take this very simple starting material with one functional group and diversify in three different positions.” This capability enables chemists to add a multitude of functional groups, in a position no other chemistry has allowed, he says.
In the new reaction, Hartwig and coworkers react their starting material with an iridium catalyst sporting 2-methylphenanthroline ligands and the borylating reagent bis(pinacolato)diboron (B2pin2) in the solvent cyclooctane. The reaction adds boronic esters at primary C–H bonds in alkanes, primary C–H bonds in unprotected alcohols, secondary C–H bonds of carbocycles, and secondary C–H bonds of saturated heterocycles, in yields of 29–85%. Hartwig used borylating reagents because the resulting C–B bonds can be converted to a plethora of different groups (shown). The scientists synthesized at least 63 compounds, from five molecule classes.
To get similar selectivity, previous C–H functionalization reactions have had to use large amounts of the starting material, often using it as the solvent. That problem limited the types of molecules chemists could modify. The speed of Hartwig’s Ir catalyst allows chemists to use less of their starting material, so the team didn’t need their target molecules to double as the solvent—meaning they could work with solids and more complex compounds. The reaction tolerates many functional groups for such a reactive catalyst, Hartwig says, which further broadens the array of potential starting materials.
This chemistry is sophisticated and clever, says organic chemist Varinder Aggarwal from the University of Bristol, who compares the reaction to expert surgery. Choosing the solvent to use in this reaction is tricky, he says, as almost all solvents have active C–H or π bonds that could themselves react. “They settled on cyclooctane, but that limits what compounds you can use since it’s a nonpolar solvent,” which not everything will dissolve in, Aggarwal says.
Hartwig agrees, and says finding a solvent that can dissolve large, polar molecules and better understanding the catalyst’s mechanism are both future goals.