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Bredt’s Rule: Why Don’t Bridgehead Double Bonds Form?

This post is all about Bredt’s Rule (1924): double听 bonds cannot be placed at the bridgehead of a听 bridged ring system. We review the key points from our chapter on cycloalkanes, dive into Bredt’s rule, explain what’s听 going on in Bredt’s rule (spoiler: poor orbital overlap between p-orbitals)听 and then (Note 1) show that听 it’s听 actually more like “Bredt’s Strongly Worded Suggestion” since there听 are indeed some molecules which possess bridgehead olefins. And we also cover bridgehead amides.

Table of Contents

1. Cycloalkanes: What We’ve Learned So Far
2. Bredt’s Rule: A Double Bond Cannot Be Placed At The Bridgehead听 Of A Bridged Ring System
3. Bredt’s Rule Explained:听 Bridgehead听 Double Bonds Have听 Poor Orbital Overlap
4. Summary: Bredt’s Rule
5. Notes
6. (Advanced) References and Further Reading

1. What We’ve Learned So Far About Cycloalkanes

At the beginning of this series on cycloalkanes听we saw that carbon’s ability to form rings leads to all kinds of interesting听consequences that follow logically from the rules of structure and bonding in organic chemistry, but nevertheless would听have been hard to predict from first principles. Among them, we’ve seen that:

• 3 and 4 membered rings have significant听ring strain (a combination of “angle strain” and “torsional strain”)
• Rings of size <8 cannot听turn inside-out, meaning that configurations of substituents relative to each other are locked. The simple way to say this is that it leads to the existence of cis and trans isomers for the disubstituted cases ( sometimes called “geometric isomers”) – e.g.听cis– and听trans-听1,2-dimethylcyclohexane.
• The most stable conformation of cyclohexane is the chair conformation in which all the groups along each C鈥揅 bond are staggered relative to each other. In the cyclohexane chair, there are two orientations of substituents on tetrahedral carbon: straight up/down relative to the ring (“axial”) and in the plane of the ring (“equatorial”).
• Cyclohexane chairs can undergo “flips” whereby all equatorial groups become axial and all axial groups become equatorial. This occurs rapidly at room temperature – so rapidly that in most cases at room temperature, the signals corresponding to each individual chair cannot be observed by our most useful tool (NMR spectroscopy) – instead, an average is observed. The activation energy for a chair flip is about 10 kcal/mol, since in order for a chair to “flip”, 听the molecule must pass through the听strained “half-chair” conformation (about 10 kcal/mol higher in energy than the chair).
• Axial substituents lead to greater torsional strain than equatorial substituents, since they experience two additional “gauche” interactions with the hydrogens on the ring carbons located two bonds away. Another way to look at the same phenomenon is to think of the axial group interacting with each of the axial hydrogens (“diaxial” interactions). For methylcyclohexane, the conformation where methyl is axial is 1.70 kcal/mol more unstable than the conformation where the methyl is equatorial, a number referred to as the “A-value” for CH₃. 听A-values have been measured for a large number of mono substituted cyclohexanes. 听In particular, the A-value for听t-butyl is so high (>4.5 kcal/mol) that cyclohexane rings with a听t-butyl substituent are essentially “locked” in the position where the听t-butyl is equatorial.
• A-values are additive. With di- and trisubstituted cyclohexanes, we can use A-values to determine which chair conformation is most stable.
• The stereochemistry of fused rings can have a huge effect on the shape of the molecule. In cis-decalin, the molecule adopts a “tent” or “cup” shape where there is a concave and convex face. Trans-decalin is much more flat. Additionally, cis-decalin can undergo chair flips on each of its cyclohexanes, but trans-decalin is “locked” in position since a ring flip would lead to too much strain (essentially this would create the equivalent of a trans-double bond in a six membered ring, which is too unstable to form).
• “Bridged bicyclic” 听and “spiro” ring junctions are also possible. 听In bridged bicyclic molecules, the two bridgeheads are separated by “bridges” containing at least one carbon. In “spiro” fused molecules, the two rings are both joined at the same carbon.

Again, even if you are a genius, it would have been extremely difficult, if not impossible, 听for you to predict all this behaviour based solely on knowing听the rules of chemical bonding. Many of these phenomena were first observed experimentally and the explanations provided post-hoc.听That’s why I keep repeating the reminder that organic chemistry is very much an empirical science.

In this , the last post on this series on cycloalkanes, we’ll talk about a final surprising and interesting consequence of the fact that carbon can form rings. 听It goes like this:

2. A double bond cannot be placed at the bridgehead of a bridged ring system听unless the rings are large enough.

Let’s go through this. Imagine drawing a version of bicyclo[2.2.1]heptane (also called “norbornane”) with 1 double bond.听

3 different constitutional isomers are possible. But only one has ever 听been observed.听

Back in 1924, German chemist Julius Bredt was working on bicyclic molecules with these (and related) ring systems, and made the following generalization:

This observation came to be known as “Bredt’s rule“. Note that no deep explanation was offered at the time – merely the observation that these bridgehead double bonds do not form.

3. Bridgehead Double Bonds Have Poor Orbital Overlap

Looking at a model, and knowing what we know now about bonding, especially that of 蟺听bonds – can you think of a reason why听bridgehead alkenes might be unstable?

Remember what is required in order for a 蟺听bond to form – we require overlap between the two adjacent p orbitals. In other words, they must be in the same plane,听lined up like the plastic men on a foosball table.

Look closely at the bridgehead C-H bond in the model above. Note how it’s almost sticking straight out to the side of the molecule, especially with respect to the C-H bond on the adjacent carbon.

The normal geometry for a sp² hybridized carbon is trigonal planar. However, due to the constraints placed on it by being part of multiple rings, the bridgehead carbon becomes “pyramidalized“, that is to say, somewhat like a pyramid (non-planar). In other words it has a very atypical shape for an sp² hybridized carbon.

Since the model above doesn’t show p-orbitals, 听I’ve taken a photo of a model where the two 听p-orbitals are roughly indicated by the bridgehead C-H bond, and red loopy looking thingy on the adjacent carbon. Note that when we look along the 听C鈥揅 bond containing the bridgehead carbon, we see that the adjacent p orbitals are “staggered” with respect to each other. In other words there听is听very little orbital overlap. Poor overlap = poor bonding! [Note 2]

Summary: Bredt’s Rule

I didn’t show what the overlap in the other possible constitutional isomer would look like (the third case in the second diagram, above) but trust me when I say that the overlap is even worse.

So the bottom line for today is听bridgehead double bonds are unstable due to poor orbital overlap.听

Here endeth the lesson for the vast majority of readers. However, if you’re interested, you can continue reading to learn about how our understanding of Bredt’s rule has evolved听since 1924.

Notes

Exceptions To Bredt’s Rule, and Bridgehead Amides

[Nov 2024]. OK, turns out the parent alkene , by inducing elimination of a silyl group and a halide through treatment with fluoride ino. Alas, as expected, the resulting bridgehead alkene is really unstable and can be trapped at very low temperature.

See: “A Solution to the Anti-Bredt Olefin Synthesis Problem”, by McDermott et. al. in Science, vol. 386 no. 6721.听DOI:

Bredt, You’ve Got It Going On听

Exceptions To Bredt’s Rule

In the intervening years the question of bridgehead double bonds has been studied in considerably more detail. The 听(academic paywall)听听although more than 30 years old, is still a very useful primer on the topic. Of particular interest is that several natural products have been isolated that contain bridgehead double bonds, such as CP-225,917 (left) and Taxol (right)

听What gives? These molecules are clearly stable. Why might bridgehead double bonds be allowed in these cases, but not in the case of norbornene, above?

It has to do with the greater flexibility that accompanies larger ring sizes. It turns out that the stability of bridgehead double bonds roughly mirrors the stability of the largest听trans-cycloalkene that contains the double bond.

Neither听trans-cyclohexene nor听trans-cycloheptene are stable enough to exist at room temperature (too much ring strain); nor have the bridgehead alkenes in a parent ring of 6 or 7 been observed as anything other than transient intermediates.

However, trans-cyclooctene is a stable molecule – and likewise, is a stable compound.. Observing bridgehead double bonds in molecules with parent ring sizes of 9 听(CP-225,917) and 10 (Taxol) is therefore to be expected, since trans-cyclononene and trans cyclodecene are stable molecules, as are all the higher cycloalkenes.

Bridgehead Amides

If you are still reading this, you must be a nerd, so one last wrinkle.

Amide bonds are generally difficult to break – certainly much more so than those of esters or acid chlorides. 听This is a good thing for us – strong peptide bonds make for stable proteins. One of the reasons is the considerable double-bond character between C and N as shown in the right-hand resonance form, a consequence of nitrogen’s considerable electron -donating ability.

What happens when the nitrogen is at a bridgehead, especially in a small ring system?

Needless to say the overlap between the lone pair on N and the carbonyl carbon is now extremely poor. This results in a 听considerably weaker C-N bond, one that is very easily cleaved by moderate nucleophiles.

In 2006 Brian Stoltz’ group at Caltech succeeded in isolating the HBF₄ salt of the . Short and interesting paper.

Note 1:听Another way of stating Bredt’s rule (once you learn about elimination reactions, is the following: “Elimination to give a double bond in a bridged bicyclic system always leads away from the bridgehead”

Bredt’s observations:

Note 2: In fact, double bonds of this type are predicted to have “diradical” character. Attempts to form bridgehead double bonds听in rings of sizes 6 and 7 are often accompanied by phenomena such as dimerization and trapping of O₂, which are clear indicators of radical intermediates.

(Advanced) References and Further Reading

1. 脺ber sterische Hinderung in Br眉ckenringen (Bredtsche Regel) und 眉ber die meso鈥恡rans鈥怱tellung in kondensierten Ringsystemen des Hexamethylens
   J. Bredt
   Justus Liebigs Annalen der Chemie 1924, 437 (1), 1-13
   DOI:
   The original paper by Bredt, noting the difficulty of synthesizing bicyclic compounds with a double bond at the bridgehead position.
2. Bredt’s Rule of Double Bonds in Atomic-Bridged-Ring Structures
   Frank S. Fawcett
   Chemical Reviews 1950, 47 (2), 219-274
   DOI:
   An old review from 1950 that compiles experimental observations to that date in support of Bredt鈥檚 Rule.
3. Bicyclo[3.3.1]non-1-ene
   James A. Marshall and Hermann Faubl
   Journal of the American Chemical Society 1967, 89 (23), 5965-5966
   DOI:
4. The Decarboxylation of 尾-Keto Acids. II. An Investigation of the Bredt Rule in Bicyclo[3.2.1]octane Systems
   James P. Ferris and Nathan C. Miller
   Journal of the American Chemical Society听1966听88 (15), 3522-3527
   DOI:
   A study of decarboxylation rates in bridged bicyclic keto acids, where the rate of decarboxylation is found to be strongly dependent on orbital overlap of the departing C-CO2H bond with the neighboring carbonyl. Good exam question material.
5. Bredt’s rule. Bicyclo[3.3.1]non-1-ene
   John R. Wiseman
   Journal of the American Chemical Society 1967, 89 (23), 5966-5968
   DOI:
   The above two back-to-back papers are on the same topic 鈥� the successful synthesis and isolation of the smallest compound with a bridgehead olefin.
6. Bredt’s rule. III. Synthesis and chemistry of bicyclo[3.3.1]non-1-ene
   John R. Wiseman and Wayne A. Pletcher
   Journal of the American Chemical Society 1970, 92 (4), 956-962
   DOI:
   This followup paper to Wiseman鈥檚 communication (Ref #4) provides more details on the synthesis and reactivity of the 鈥楢nti-Bredt鈥� olefin, bicyclo[3.3.1]non-1-ene.
7. Bredt Compounds and the Bredt Rule
   Dr. Gert K枚brich
   Angew. Chem. Int. Ed. 1973, 12 (6), 464-473
   DOI:
   As the structural basis for Bredt鈥檚 Rule became clear, it was evident that the prohibition against bridgehead double bonds would not be absolute.
8. Recent developments in the synthesis, structure and chemistry of bridgehead alkenes
   Kenneth J. Shea
   Tetrahedron 1980, 36 (12), 1683-1715
   DOI:
   This review summarizes work that took place after Fawcett鈥檚 review (Ref #2) and includes information on the successful synthesis of compounds with bridgehead alkenes.
9. Strained bridgehead double bonds
   Philip M. Warner
   Chemical Reviews 1989, 89 (5), 1067-1093
   DOI:
   A more recent review, this includes information on the successful synthesis of 鈥榓nti-Bredt鈥� hydrocarbons.
10. Natural Products with Anti鈥怋redt and Bridgehead Double Bonds
    Jeffrey Y. W. Mak Dr. Rebecca H. Pouwer Assoc.鈥匬rof. Craig M. Williams
    Angew. Chem. Int. Ed. 2014, 53 (50), 13664-13688
    DOI:
    This review covers the synthesis of natural products with bridgehead olefins. Compounds that have bridgehead double bonds and are otherwise stable are also known as 鈥楢nti-Bredt鈥� olefins, since they defy Bredt鈥檚 Rule.
11. Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate
    Tani, K., Stoltz, B.
    Nature 2006, 441, 731鈥�734
    DOI:
    A landmark paper on the synthesis and unambiguous characterization (by X-ray spectroscopy) on potentially the smallest bridgehead amide.
12. Formation of Anti-Bredt Olefins from Bridgehead Carbene Precursors:鈥� A Computational Study
    Michael Geise and Christopher M. Hadad
    Journal of the American Chemical Society 2000, 122 (24), 5861-5865
    DOI:
    This paper examines computationally whether 鈥楢nti-Bredt鈥� olefins can be formed by formation of the bridgehead carbene followed by rearrangement. In the conclusion, the paper states, 鈥�this study has shown that the equilibria for rearrangement of bridgehead carbenes to anti-Bredt olefins lie heavily on the side of the olefin. Also, the calculated intrinsic barriers to rearrangement are all easily accessible under most reaction conditions, with the largest barrier being 7.4 kcal/mol鈥�. Now, all we need is experimental evidence!
13. Does 1鈥怤orbornene Exist?
    R. Keese and E.鈥怭. Krebs
    Angew. Chem. Int. Ed. 1972, 11 (6), 518-520
    DOI:
    1-norbornene, the smallest bicyclic bridgehead olefin which has been investigated experimentally, has not been directly observed or characterized. Instead it has been trapped as an adduct with furan, suggesting that it formed as an intermediate.
14. Evaluation and prediction of the stability of bridgehead olefins
    Wilhelm F. Maier and Paul Von Rague Schleyer
    Journal of the American Chemical Society 1981, 103 (8), 1891-1900
    DOI:
    This is a rather comprehensive computational study. Prof. Schleyer has calculated the strain energy and heat of formation of >50 bridgehead olefins, in order to determine trends based on structure.
15. A Solution to the Anti-Bredt Olefin Synthesis Problem
    McDermott, L. et. al.
    Science,听2024,听386, 6721, xxxx