Some rules can be broken! Sometimes it takes longer!
"A new study by UCLA organic chemists shows how to create several types of molecules that violate Bredt’s rule, known as anti-Bredt olefins (ABOs). Many modern textbooks and online resources describe ABOs as being “too unstable to form” or “forbidden”. The research provides chemists with practical methods to synthesize and utilize ABOs in reactions, 100 years after “Bredt’s Rule” originated. ...
Key takeaways
- According to Bredt’s rule, double bonds cannot exist at certain positions on organic molecules if the molecule’s geometry deviates too far from what we learn in textbooks.
- This rule has constrained chemists for a century.
- A new paper in Science shows how to make molecules that violate Bredt’s rule, allowing chemists to find practical ways to make and use them in reactions.
..."
From the editor's summary and abstract:
"Editor’s summary
One hundred years ago, Julius Bredt published an observation that certain molecules that constrained several adjacent carbon centers in a particular nonplanar arrangement could not form double bonds between them. These hypothetical double bonds became known as “anti-Bredt” olefins, and the doctrine that they were inaccessible remains widespread even with the occasional hint to the contrary. McDermott et al. now report a general strategy to prepare these olefins as fleeting intermediates that can be captured in cycloaddition reactions. The protocol relies on the driving force of silicon-fluorine bond formation from a precursor, which is akin to approaches used to access strained aromatics. ...
Structured Abstract
INTRODUCTION
The π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading to heightened reactivity of the π-bond. Although π-bond–containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of π-bond–containing compounds that display twisting or pyramidalization remains underdeveloped. One of the most notorious classes of π-bond–containing compounds that feature twisting and pyramidalization are anti-Bredt olefins (ABOs), which conventional wisdom maintains are difficult or impossible to access. We sought to realize a solution to the long-standing problem of synthesizing and manipulating ABOs.
RATIONALE
The study of ABOs began at the dawn of the 20th century with Julius Bredt’s derivatization studies of the camphane and pinane ring systems. These studies eventually led to Bredt’s 1924 conclusion that a carbon-carbon double bond could not arise from the branching positions of the carbon bridge, which is now known as “Bredt’s rule” in the context of strained systems. Despite Bredt’s conclusion, many endeavors toward generating ABOs transiently have been made over the past century. These studies support the existence of ABOs but also suggest that ABOs are often unstable and prone to decomposition. ABOs are still often considered inaccessible synthetic intermediates per modern resources. A solution to the long-standing problem of accessing and intercepting ABOs would challenge Bredt’s rule, provide a new entryway to access substituted bridged bicycles, and highlight the potential of strategically leveraging geometrically distorted alkenes for use in chemical synthesis.
RESULTS
Inspired by the Kobayashi approach toward benzyne and its successful application to other strained intermediates, we evaluated silyl (pseudo)halide precursors to a number of different ABOs. Treatment of these precursors with a fluoride source, such as Bu4NF or CsF/Bu4NBr, in the presence of a suitable trapping agent, led to cycloadducts indicative of an ABO being generated in situ and undergoing trapping. This strategy was applied to several bicyclic ring systems, such as [3.2.1], [2.2.2], and [2.2.1] ABOs. In all cases, we evaluated the geometric distortion associated with the ABO π-bond using density functional theory computations, showing that the alkenes of ABOs indeed display twisting and pyramidalization. In the context of a [2.2.1] ABO, we show that this geometrically distorted structure could be used in a variety of trapping experiments, including (4+2), (2+2), (3+2), and (5+2) cycloadditions. These trapping experiments show that ABOs can provide access to structurally complex products, including those that bear functional handles poised for further manipulation.
Computational studies were performed to better understand the high reactivity of ABOs, with a focus on the [2.2.1] bicyclic structure. These studies support the notion that ABOs have distinctly olefinic character and react in a concerted asynchronous cycloaddition with dienes such as anthracene. Stereochemical studies on the [2.2.2] bicyclic system show that point chirality present in a precursor can be transmitted to deliver point chirality in a cycloadduct by way of an axially chiral intermediate. This provides experimental support for the olefinic character present in ABOs.
CONCLUSION
These studies show that highly strained ABOs can be made and intercepted in situ, thus providing a solution to the long-standing problem of ABO generation and trapping. Additionally, our findings highlight the potential of strategically leveraging the heightened reactivity of geometrically distorted alkenes for broad use in synthesis."
Organic chemists take on “Bredt’s Rule” 100 years later (original news release)
Summary of Bredt’s original findings from the early 1900s and the establishment of Bredt’s rule (left). Examples of ABOs synthesized in this study, all of which were validated through trapping experiments (right, top). Transfer of point chirality in a precursor to point chirality in the product by way of an axially chiral intermediate provides experimental evidence for the intermediacy of the twisted [2.2.2] ABO (right, bottom). Me, methyl; DMF, N,N′-dimethylformamide; ee, enantiomeric excess.
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