Issue Date: April 11, 2011
A new carbon monoxide-generating reagent and an associated reaction system could make lab-scale carbonylation reactions easier by simplifying purification and safer by eliminating virtually any possibility of exposure to dangerous CO gas.
Carbonylation—introducing CO into substrates—is widely used for the synthesis of aldehydes, carboxylic acids, esters, amides, and other compounds. But CO is a toxic gas. If inhaled, it excludes oxygen from hemoglobin, causing asphyxiation. Protective measures in industry enable use of CO gas in that setting. But using CO in small R&D and academic labs is much less common because it requires expensive, specialized equipment.
Now, postdoc Anders T. Lindhardt, synthetic organic chemist Troels Skrydstrup, and coworkers at Aarhus University, in Denmark, have developed a solid acid chloride compound that can be safely handled and stored and then used in a sealed two-chamber reaction vessel to carry out small-scale carbonylation reactions (J. Am. Chem. Soc., DOI: 10.1021/ja200818w). A palladium catalyst releases CO from the acid chloride in the first chamber, and a second palladium catalyst introduces CO into a starting material in the second chamber.
“People are afraid of CO, which is toxic, flammable, and difficult to work with,” says Mats Larhed of Uppsala University, in Sweden, an expert on CO-releasing reagents. “So carbonylation is not used as much as it should be in lab-scale organic synthesis.”
Researchers have developed a number of CO-releasing carbonylation reagents to sidestep this problem. But these reagents are mixed with the compounds to be carbonylated, necessitating purification of carbonylation products to remove unwanted by-products of CO generation.
The Aarhus researchers demonstrated their new procedure by using it to carry out aminocarbonylations of several organic starting materials to produce compounds of potential pharmaceutical interest. They also used an isotopic variant of the acid chloride to carbonylate compounds with carbon-13 for labeling studies.
The two-chamber technique “is definitely a new way” of carbonylating compounds, Larhed says. “This is the first time I’ve seen this type of approach, and it’s quite smart.” Because it uses palladium catalysts, “I do not think it will be cheaper than existing alternatives” based on carbonylation reagents such as molybdenum hexacarbonyl, he says. “But the method will help researchers run clean small-scale carbonylations without gas tubes, and it will be valuable in carbon-13 labeling work.”
The need to use a two-chamber flask can also be seen as a drawback of the technique, Larhed notes. But, he adds, the method “will help in purifying products because you don’t have to remove the CO source material from the product mixture.”
The technique “seems to work in a broad range of carbonylations, which is very impressive,” Larhed says. “I think it will have broad utility.”
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