Inventive technique transforms a common reagent into a multifunctional tool for pharmaceutical synthesis

Nov 20, 2013

Calcium carbide (CaC2) is a simple molecule used worldwide to produce industrial-scale quantities of the fuel known as acetylene gas (see image). Chemists have found ways to generate CaC2 from sustainable biomass resources, making this compound even more attractive as a fundamental 'building block' for organic chemistry. Direct use of CaC2 as a synthetic reagent, however, is rare because it has poor solubility in most organic solvents.

Yugen Zhang and co-workers from the A*STAR Institute of Bioengineering and Nanotechnology, Singapore, are now set to resolve this solubility problem. They have developed a new protocol that uses CaC2, a copper catalyst and a dash of water to produce an important synthetic intermediate for pharmaceutical compounds1.

Enaminones are organic compounds that link amines and carbonyl chemical groups through an unsaturated carbon double bond. This arrangement gives enaminones both electron-repelling (nucleophilic) and electron-attracting (electrophilic) capabilities, which are useful during the synthesis of complex drugs that mimic natural biological products. Typically, however, chemists take multiple steps to construct these multifunctional reagents.

Zhang and co-workers recently developed a catalytic route that turns CaC2 into propargylamines—molecules with acetylene, alkyl and amine groups—by dissolving it with highly polar . Under certain conditions, the team noticed that small amounts of enaminones were also produced—a finding that suggested liquid acetylide ions (C22-) could act as a bridge to connect nucleophilic and electrophilic chemicals in a single reaction pot.

When the team investigated a three-way catalytic coupling between acetylide ions, an amine, and an aldehyde, they saw an extraordinary dependence on solvent choice. Acetonitrile, a nitrogen-bearing solvent, yielded predominantly propargylamines, while dimethylformamide (DMF)—a solvent that contains aldehyde and amine groups—produced the enaminone targets. Intriguingly, a fractional 1% addition of water to the DMF solvent rapidly sped up enaminone production.

Mechanistic experiments revealed that water molecules, besides improving the solubility of CaC2, also acted as a proton source that helped to generate enaminones from a catalytic copper complex. Furthermore, the team discovered that they could also fine-tune their synthesis by changing the size of their starting materials: bulky amine reagents tended to provide the kinetic conditions needed to bridge nucleophilic and electrophilic units.

Zhang notes that the cost-effectiveness and efficiency of these findings could make researchers rethink the role of CaC2 in modern . "Chemistry is extremely versatile and we can expect surprising results," he says. "Just because a reaction has not yet occurred does not mean that it will never happen in the future."

Explore further: Researchers bring clean energy a step closer

More information: Yu, D., Sum, Y. N., Ean, A. C. C., Chin, M. P. & Zhang, Y. Acetylide ion (C22-) as a synthon to link electrophiles and nucleophiles: A simple method for enaminone synthesis. Angewandte Chemie International Edition 52, 5125–5128 (2013).

add to favorites email to friend print save as pdf

Related Stories

Building better molecules for bendable electronics

Oct 11, 2013

Organic semiconductors made from small aromatic molecules can be dissolved and screen-printed onto many substrates, including plastics, opening the path for 'flexible' electronic devices such as low-cost ...

Recommended for you

Researchers bring clean energy a step closer

Feb 27, 2015

For nearly half a century, scientists have been trying to replace precious metal catalysts in fuel cells. Now, for the first time, researchers at Case Western Reserve University have shown that an inexpensive metal-free catalyst ...

The construction of ordered nanostructures from benzene

Feb 27, 2015

A way to link benzene rings together in a highly ordered three-dimensional helical structure using a straightforward polymerization procedure has been discovered by researchers from RIKEN Center for Sustainable ...

Superatomic nickel core and unusual molecular reactivity

Feb 27, 2015

A superatom is a combination of two or more atoms that form a stable structural fragment and possess unique physical and chemical properties. Systems, that contain superatoms, open a number of amazing possibilities ...

NETL invents improved oxygen carriers

Feb 24, 2015

One of the keys to the successful deployment of chemical looping technologies is the development of affordable, high performance oxygen carriers. One potential solution is the naturally-occurring iron oxide, ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.