Meta Reaction Revisited

A copper conundrum has researchers reevaluating how some counterintuitive chemistry really works.

Last year, Robert J. Phipps and Matthew J. Gaunt of the University of Cambridge generated excitement with their report of a copper-catalyzed process that dodged the laws of electrophilic aromatic substitution—a fundamental reaction in organic synthesis (Science, DOI: 10.1126/science.1169975; C&EN, March 23, 2009, page 7). C&EN featured this work as one of 2009’s top achievements in its Chemical Year in Review (C&EN, Dec. 21, 2009, page 35). But more recent results suggest that copper isn’t always necessary for the reaction to proceed, thereby leaving the reaction’s mechanism unclear.

Electrophilic aromatic substitution reactions replace the hydrogen atoms on aromatic rings with other functional groups, and time-honored rules predict how substituents already on the rings influence what the reaction products will be. Crafty chemists have developed a few ways to skirt these rules, but making meta-substituted rings isn’t always easy.

In 2009, Phipps and Gaunt reported a new way to make meta-substituted rings, starting from aromatic rings featuring a traditionally ortho/para directing group, acyl amines. At the time they published their work, a copper salt seemed key to the unusual selectivity. They suggested a possible mechanism that involved an electron-poor copper(III) species.

This fall, the team extended their meta-selective process to additional aromatic substrates (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201004704). But they noticed copper wasn’t always required to obtain meta-substituted products. When they ran their reaction at 70 °C, conditions identical to those from the study published in Science, they did not obtain meta-substituted products unless they added a copper salt, Gaunt says. But when they raised the reaction temperature by 10 or 20 degrees, in order to see whether elevated temperatures affected meta selectivity, they obtained meta-substituted products without adding any copper salts.

The new results make the copper(III) mechanism unlikely, Gaunt says. “The copper is probably not responsible for the meta selectivity, but it’s certainly a catalyst in the reaction,” he says. “The reaction works in better yields and at lower temperatures in the presence of copper.”

The new findings don’t change the fact that the process gets around some classic rules of organic chemistry, Gaunt says. “All that has changed is that our proposed hypothesis for the mechanism is probably not correct,” he says. “We hope that a new understanding of the role of the copper catalyst will help us to identify new synthetically useful reactions.”

The new results prompted a heated discussion in the comments section of the organic chemistry blog “Totally Synthetic.” Remarks in the comments section questioned whether the Cambridge team performed the proper controls before publishing the 2009 Science paper. They also suggested alternative reaction mechanisms and suggested a retraction or correction of the paper was in order. Science has not been contacted regarding Phipps and Gaunt’s 2009 publication, says Jake S. Yeston, a senior editor at the journal whose areas of responsibility include chemistry.

The blog comments section raises interesting arguments but none that invalidate Phipps and Gaunt’s paper, says organometallic chemist Robert Maleczka Jr. of Michigan State University, who wrote a commentary on the meta-selective reaction for Science last year (DOI: 10.1126/science.1172298). “I think for the Science paper, the controls that were done were appropriate,” he says. “It would be unusual for a team to have conditions that are working and then do another set of controls for suboptimal conditions” right away, he adds. Many factors affect decisions about which experiments to conduct when, and in the Cambridge team’s case, one factor may have been that the class of reagents that provide the new meta substituent can produce unstable intermediates at higher temperatures, he says. Maleczka speculates it wasn’t unreasonable to wait on performing higher temperature experiments.

In addition, a preliminary literature search suggests the Cambridge team’s reaction has a different product distribution than would be expected from the mechanisms proposed in the blog comments section, including traditional Friedel-Crafts electrophilic substitution chemistry, Maleczka says.

“I do not view [the new reaction] as a retraction,” adds synthetic chemist Mark Lautens of the University of Toronto. “Higher temperatures can often promote certain kinds of reactions that otherwise fail,” he says.

“It is certainly interesting that the switch from copper-promoted to thermal reactions is so dramatic and occurs over a narrow temperature range,” Lautens says. The team “has a lot more work to do now to figure out what is going on and to see if any trace amount of a catalyst is promoting the reaction.”

“While it is not impossible that the reaction is the result of ultralow metal impurities we do not have any evidence to support this,” Gaunt says. His team plans to publish further studies on the reaction mechanism.

“This is the early sunrise of a new method,” says Victor Snieckus of Queen’s University, in Kingston, Ontario, whose work in directed ortho metalation has led to useful routes to polysubstituted aromatic rings. “Like rock stars, reactions can come and go, but those with substance achieve greatness,” he adds. Most new reactions have to experience a gestation period so the process has a chance to mature into something useful to many chemists, he says.

“This is just cool chemistry,” Maleczka says. “If you waited to publish until you fully understood everything, you’d never publish anything.”