Bredt’s rule states that double bonds do not occur at bridgeheads of bridged rings.

BUT: “Anti-Bredt olefins” defy this rule. They are not often talked about, but chemists have known them for decades.
In this post, we explain when Bredt’s rule becomes invalid – a good read for any student willing to go beyond their curriculum. This is particularly relevant as recent news headlines touted the “synthesis of impossible molecules” by chemists. More visuals can be found in my video on this topic.

Interactive 3D model of 1-norbornene, an anti-Bredt olefin

BredT’s rule: History and its original form

To understand Bredt’s rule, we need to go back in time. Julius Bredt was one of the oldschool German chemists of the 19th century, and much of his early work centered on the molecule camphor. This pleasantly smelling terpenoid natural product is found in camphor and other trees, and saw a move towards large scale use for the plastics industry in the 1870s. Various chemists proposed pretty freaky structures, including the legendary August Kekulé.

However, it was Julius Bredt who identified camphor’s real structure with a bridged bicyclic ring system. He would spend years validating his findings and correcting the errors of his predecessors.

Bredt’s famous rule originated from his in-depth camphor studies, as he was not able to synthesize certain derivatives as planned. One of the first examples was this anhydride with a double bond at the bridged position. Elimination of a brominated precursor, or alternatively a condensation reaction of an unsaturated precursor did not prove fruitful. After many synthetic attempts and encountering more quote unquote impossible olefins, Bredt formalized his guideline: bridgehead atoms of bridged rings cannot engage in double bonds.

Ring Strain in Bredt’s Rule

In his seminal 1924 paper, Julius Bredt had already correctly stated that ring strain is behind the apparent impossibility of these olefin compounds. But what is the source of that ring strain, and when is this rule really valid? And how strained are these forbidden rings really?

So we all know that a normal olefins are completely flat with a co-planar arrangement of substituents. However, involving a bridgehead creates an (E)-alkene where a substituent on one carbon is connected to a substituent on the other carbon.

If there are only few carbon atoms in this bridge, they would need to stretch out to ridiculous proportions to accommodate for this planar geometry. So, the molecule tries to find a middle ground regarding ring strain and distortion. This means our double bond is not coplanar but actually twisted. This twisting leads to a suboptimal overlap of the p-orbitals in the pi-bond, which is also destabilizing.

Speaking of p-orbitals, remember how normal alkenes are sp2 hybridized? In the anti-Bredt olefin, we see significant rehybridization to sp3 character as the carbons are pyramidal. This reorientation is key to boost the bond order to a surprisingly high value of 1.86. We have good evidence to believe this is a legit double bond and not something like a di-radical – more on this later.

We have seen why this system is destabilized or strained, but how strained is it? You might know that some thermodynamics shenanigans called homodesmotic equations can help out. Essentially, we are comparing the total strain energies of the saturated and unsaturated molecules to evaluate the pure strain contribution of the anti-Bredt double bond.

Such computations were established in the 1980s, as physical organic chemists tried to understand the limits of these olefins based on their size and strain energy.
Here it becomes useful to quantify the size of a bridged ring by simply adding up the number of atoms in the bridges (referred to as S).

The pioneers found that the ring strain estimation can pretty accurately predict if an olefin is stable at room temperature, if it’s olefin observable only at lower temperatures, or if it’s so unstable that we can’t form it or observe it at all.

Key takeaway: Small bridged rings are very strained while larger bridged rings can increasingly accommodate the desired olefin geometry without all the energy penalties. This is why Bredt’s rule loses its validity in larger rings!  

Quick knowledge test

Let’s briefly check whether you understood the concept or not. A typical exam question goes along the lines of: Does the alkene shown below violate Bredt’s rule? Look at the four olefins below and identify if they violate Bredt’s rule. Why (not)?

First examples of Anti-Bredt Olefins

The quest to find such larger rings (which don’t obey Bredt’s rule) started in the mid-20^th century, with notable efforts from chemists Prelog and Ruzicka. Over time, chemists figured out that such rings even occur in natural products. Prominent examples are the anti-cancer compound taxol or the CP molecules which have a ring size S = 8.

Over the last decades, chemists brought forward clear evidence for these anti-Bredt olefins, even ones with S values below 7. Most of these used trapping experiments to capture short-lived anti-Bredt olefins, like 1-norbornene. In this case, the chemists ran a lithium-halogen exchange reaction of a di-halo precursor in the presence of furan. As they isolated the corresponding Diels-Alder adducts, it seems reasonable to assume that an anti-Bredt olefin with S = 5 was formed and very rapidly intercepted by furan.

Even more impressive is the case of this anti-Bredt olefin with S = 7. Considering the delicate nature of the product, it seems really ironic that the chemists made it by brute-force pyrolyzing this quaternary ammonium precursor through a Hofmann elimination. They also did some nice trapping, but even managed to get NMR data at -80 °C. This is really remarkable and only case to date of a theoretically unstable anti-Bredt olefin being observed directly. Evidently, using the total ring size S as proxy for stability does not work every time.

“Solution to the Anti-Bredt Olefin Synthesis Problem”?

So, we see that the question is not if anti-Bredt olefins can be made, but rather if there are more practical and useful approaches than what we know already. We might not be content with having to incinerate our molecules to get crappy yields of product in a soup of unwanted side products (e.g., due to their low stability, anti-Bredt olefins can intramolecularly rearrange).

Recent research by Garg used fluoride-mediated elimination to create the anti-Bredt olefins, but found that the relative stereochemistry was critical. You see, the precursor with an equatorial silyl group proved unreactive even under forcing conditions while its diastereomer was more useful. By computing the structures, the chemists realized that the reactive diastereomer features a relatively smaller angle between the silyl electrofuge and the leaving group. Because this is a syn-elimination that requires overlap of the carbon silicon sigma and the carbon-oxygen sigma star orbitals, a narrow angle is better. The equatorial diastereomer has a very large angle and low overlap, suppressing any reactivity.

The chemists optimized the conditions by using anthracene as a trapping agent. They found success with a low temperature option using the classic fluoride source TBAF, or alternatively a high-temperature option using a slow-release source of TBAF which helps to control the reaction. The high yield is remarkable as you would expect 16 hours at 120 °C to cause quite some damage. Well, it does not, and the experimental procedure is pretty simple.

So what’s the scope of this method? Other trapping agents were less efficient but still a major improvement to what we knew before – we have furan and its aromatic friends, as well as 1,3-dipoles. They also saw good breadth in terms of anti-Bredt olefins, with some larger and functionalized rings being tolerated. If you are paying attention, you will have noticed that the figure reports diastereomeric ratios of products. But what stereoselectivity does this even refer to?

Our anti-Bredt olefin is actually one specific diastereomer with the hydrogen retaining a pseudo-axial position after the initial elimination.

Remember how we said that instead of a coplanar geometry, we said the system is twisted to a significant degree? Well, the epi diastereomer with a pseudo-equatorial hydrogen would be even more distorted with larger twisting angles and pyramidalization. This elevates its energy and explains why we don’t see any cycloaddition adducts with an equatorial hydrogen at this carbon.

What happens if we use an olefin precursor with just one chiral center?

Here, the chemists synthesized the symmetrical [2.2.2] ring with high enantiometric excess through separation of diastereomeric derivatives. We’ve already seen the diastereoselectivity and stereospecificity of the reactions so it shouldn’t be too surprising: The chirality is fully transferred to the cycloadduct. This once again suggests a concerted elimination step and a chiral alkene with high barrier to racemization and a low, if any, diradical character of the anti-Bredt olefin.

Conclusion

So, we’ve known about small anti-Bredt olefins for a long time. This means Bredt’s rule was already plenty broken in the past. The new research confirms the current interpretation of Bredt’s rule: small olefins are unstable but not necessarily impossible to form. However, the new research adds very practical experimental methods and deeper computation understanding. Thus, anti-Bredt olefin intermediates might get into reach of synthetic chemists. However, the structures of the trapping products are not common so the utility is currently debatable. Maybe, this will encourage more rule-breaking in other areas. Only time will tell!

References on Bredt’s Rule

• Generation of strained alkene by the elimination of .beta.-halosilane. On the nature of the double bond of a bicyclo[2.2.2] bridgehead alkene | JACS 1977, 99, 936
• A solution to the anti-Bredt olefin synthesis problem | Science 2024, 386, eadq3519
• Total Synthesis of Natural Products Containing a Bridgehead Double Bond | Chem 2020, 6, 579
• Evaluation and prediction of the stability of bridgehead olefins | JACS 1981, 103, 1891
• Do Anti-Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability | ACIE 2015, 54, 10608