CAS: Metal-Free Cyclobutadiene Reagents for Organic Synthesis

With the support of the Chemical Synthesis program in the Division of Chemistry, Professor Noah Burns of Stanford University will study the development of practical chemical reagents for generating and utilizing cyclobutadiene in organic synthesis. Cyclobutadiene is an exceptionally reactive species that has seen significant applications in the construction of small molecules and materials.

Despite this, chemists have continued to use the same technologies for its production that were developed over 50-years ago. These outdated processes involve numerous chemical reactions, hazardous heavy metals, and costly starting materials. This funding will allow the Burns research group to develop new reagents that can be efficiently produced in multigram quantities without the use of toxic heavy metal reagents.

These reagents are designed to controllably release cyclobutadiene under environmentally benign conditions and allow for the synthesis of cyclobutadienes that have not been previously explored. This work is expected to have significant impacts in the field of organic synthesis and the broader chemical sciences as it will not only advance our understanding of fundamental chemical processes involved in making and using the new reagents but also pave the way for practical applications towards naturally occurring molecules, the synthesis of biologically active compounds, the creation of novel materials, and the production of energy-dense assemblies.

Broader impacts of this work include cultivating an interdisciplinary training environment as well as outreach efforts aimed at attracting younger students to a future in STEM. This funding will also help support underrepresented students who have not yet had access to R1 university resources by providing them with research opportunities at Stanford.

The central goal of this project is to establish diazabicyclohexene dicarbamates as robust, metal-free precursors to reactive cyclobutadiene species. These novel reagents can be synthesized reliably and on large scale from simple, inexpensive starting materials. Upon hydrolysis and treatment with a mild oxidant, they can be triggered to extrude carbon dioxide and nitrogen gas, releasing reactive cyclobutadienes.

Initial studies in the Burns group have successfully validated this approach, demonstrating its facile ability to produce and engage cyclobutadiene with electron-deficient dienophiles in Diels–Alder cycloadditions under an ambient atmosphere and in the presence of water – conditions that were not possible with previous metal-based cyclobutadiene reagents. As opposed to heavy metal waste produced with earlier methods, this reaction produces only innocuous organic byproducts.

Future research efforts will be aimed at synthesizing a broader library of substituted cyclobutadiene precursors bearing previously inaccessible substitution patterns including halogen atoms and heteroatom functionalities. Complementary computational studies will guide the rational design of these reagents and provide insights into the associated reaction mechanisms and origins of selectivity.

Synthetic applications that will be pursued include the total synthesis of (poly)cyclobutane-containing natural products, the synthesis of strained hydrocarbon targets, and the assembly of mechanochemically responsive ladder polymers. This research program has the potential to establish a new paradigm for cyclobutadiene generation and promises to expand the pool of molecular structures and materials that are synthetically accessible via cyclobutadiene cycloaddition pathways.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.