An Overview about the Fulvenes, their cycloaddition mechanism and their applications

1. An Overview of Cycloaddition of
Fulvenes and Emerging
Applications
-MINHAJ SOHAIL SHAKIL PATEL
(MC/2019/15)

2. CONTENTS
Introduction
Properties of Fulvenes
Fulvene Cyclo-additions
Dimerization Cyclo-additions
Intra-molecular Cyclo-additions
Inter-molecular Cyclo-additions
Applications
References
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3. INTRODUCTION
• Cyclic conjugated systems involving an exo-methylene unit in the ring system are
generally termed fulvenes
• Fulvenes are an interesting organic class of cross-conjugated, cyclic molecules first
discovered by Thiele in 1900, with the preparation of pentafulvenes by
condensation of aldehydes and ketones with cyclopentadien
• Most commonly encountered are pentafulvenes, although tria-, hepta- and nona-
fulvenes have also been studied
• Historically, fulvenes were of great interest as a result of their unique reactivity
resulting from their exocyclic double bond
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition
chemistry of fulvenes and emerging applications. Beilstein Journal of
Organic Chemistry. 2019 Sep 6;15(1):2113-32.
3

4. Properties of Fulvenes
Fulvenes are
thermally
unstable
Fulvenes are
sensitive to
oxygen
Fulvenes are
photosensitive
Fulvenes
react with
both
electrophile
and
nucleophile
Fulvenes
readily
participate in
cyclo-addition
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of fulvenes
and emerging applications. Beilstein Journal of Organic Chemistry. 2019 Sep
6;15(1):2113-32.
4

5. Polarizability of Fulvenes
• The exocyclic double bond of fulvene easily gets polarised giving rise to
dipolar resonance structures
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of fulvenes and
emerging applications. Beilstein Journal of Organic Chemistry. 2019 Sep 6;15(1):2113-32. 5
Resonance Structures of Pentafulvenes
Resonance Structures of Heptafulvenes

6. Effect of Substituents on Fulvenes
• The nature of the substituents on the exocyclic carbon influences the fulvene
reactivity and stability
• Penta-fulvene derivatives, when substituted with electron-withdrawing groups
(EWG) (e.g., CN) or electron-donating groups (EDG) (e.g., O, N) on the exocyclic
C6-position, exhibited antiaromatic and aromatic ring currents, respectively
• Substituents of an electron-donating nature (e.g.,NH2, OH) generally increases the
reaction rate through stabilisation of the Diels–Alder transition state, while those
which are electron-withdrawing (e.g., NO2, Halogens) decreased the reaction rate
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of
fulvenes and emerging applications. Beilstein Journal of Organic Chemistry.
2019 Sep 6;15(1):2113-32.
6
EDG= NH/NR, OH/OR, CH/CR
EWG= X, CO, NO2, NR

7. Fulvenes Cycloaddition Mechanism
 Two independent π-systems combine to form a cyclic compound in which the
creation of two new σ-bonds occur are called as cyclo-addition reactions
 These reactions are also known as “[m+n]” cyclo-addition reactions
where, m=No. of π electrons present in one unsaturated molecule
n=No. of π electrons present in other unsaturated molecule
 Example:
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8. Types of Fulvenes Cycloadditions
Dimerization
Cycloadditions
Intra-
molecular
Cycloadditions
Inter-molecular
Cycloadditions
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9. Dimerization
 Dimerization of fulvenes is an undesired process that may occur upon storage, or
compete during reactions with other substrates
 Above -75 ⁰C, the 1H NMR signals of methylenecyclopropene began to diminish
with the concomitant formation of new signals arising from the head-to-tail dimer
12/3/2019
Billups WE, Gesenberg C, Cole R. A new methylenecyclopropene synthesis and
the isolation of a novel methylenecyclopropene dimer. Tetrahedron letters. 1997
Feb 17;38(7):1115-6.
9

10. Pentafulvene Dimerization
 Penta-fulvene Dimerization
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition
chemistry of fulvenes and emerging applications. Beilstein Journal of
Organic Chemistry. 2019 Sep 6;15(1):2113-32.
10
Dimerization of pentafulvenes via a Diels–Alder cycloaddition pathway whereby one fulvene acts as a diene and
the second fulvene acts as a dienophile.

11. Intra-molecular Cycloadditions
 For the intra-molecular cycloadditions of pentafulvenes, the fulvene has been
reported to react as both diene and dienophile
Example:
 Pentafulvenes attached to various dienes have been employed as precursors to
various polycyclic ring systems, including kigelinol, neoamphilectane and kempane
skeletons
12/3/2019
Moideen SV, Houghton PJ, Rock P, Croft SL, Aboagye-Nyame F. Activity of extracts and
naphthoquinones from Kigelia pinnata against Trypanosoma brucei brucei and Trypanosoma
brucei rhodesiense. Planta medica. 1999 Aug;65(06):536-40.
11

12. Intra-molecular Cycloadditions
12/3/2019
Weinreb SM. Alkaloid total synthesis by intramolecular imino Diels-Alder cycloadditions.
Accounts of Chemical Research. 1985 Jan 1;18(1):16-21.
12

13. Intra-molecular Diels-Alder Cycloaddition
• The treatment of fulvene in the presence of lithium perchlorate in Diethyl ether as a
medium at room temperature for 30 minutes led to unspecific decomposition and no
product could be isolated, leading to a failure of Intra-molecular Diels-Alder
reaction.
12/3/2019
Weinreb SM. Alkaloid total synthesis by intramolecular imino
Diels-Alder cycloadditions. Accounts of Chemical Research.
1985 Jan 1;18(1):16-21.
13

14. Intra-molecular Diels-Alder Cycloaddition
• The success of Intra-molecular Diels-Alder reaction is due to the stearic bursting
effect.
12/3/2019
Weinreb SM. Alkaloid total synthesis by intramolecular imino Diels-Alder cycloadditions.
Accounts of Chemical Research. 1985 Jan 1;18(1):16-21. 14

15. Inter-molecular Cycloadditions
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of
fulvenes and emerging applications. Beilstein Journal of Organic Chemistry.
2019 Sep 6;15(1):2113-32.
15

16. Inter-molecular Cycloadditions
 Diels-Alder Inter-molecular Cycloaddition
• Because of energetically strained 4-membered ring inevitably undergoes subsequent
ring-opening , in the [4 + 2] cycloaddition the triafulvene could only be generated
in situ from methyl(2-methylenecyclopropyl)(phenyl)sulfonium tetrafluoroborate
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry
of fulvenes and emerging applications. Beilstein Journal of Organic
Chemistry. 2019 Sep 6;15(1):2113-32.
16

17. Inter-molecular Cycloadditions
 Scope of Fulvenes in Inter-molecular cycloadditions with different reactant partners
:-
12/3/2019Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of fulvenes and
emerging applications. Beilstein Journal of Organic Chemistry. 2019 Sep 6;15(1):211
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18. Applications
A. Organic and natural products synthesis
• Penta-fulvenes appear to be the only fulvenes used in this approach, likely due to
their relative stability compared to other members of the fulvene family, diverse
cycloaddition chemistry, and easy access
• Pentafulvenes have been used as key reactants for the synthesis of natural products
and their skeletons
• Each of these natural products are biologically active, hence their total synthesis
will allow further characterisation of their reactivity and mechanisms of action
• The synthesis of the listed organic molecules (listed in Table ) is generally
successful, with high yields in almost all cases. However, some of these synthetic
pathways are multistep, hence require optimisation for viability and large-scale
production
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition
chemistry of fulvenes and emerging applications. Beilstein
Journal of Organic Chemistry. 2019 Sep 6;15(1):2113-32.
18

19. Examples of molecules synthesized from fulvenes

20. Applications
B. Dynamic Combinitorial Chemistry
• DCC is a method to the generation of new molecules formed by reversible
reaction of simple building blocks under thermodynamic control. As the reactions
are reversible, several different structures are possible and the system exists in
equilibrium
• Upon the addition of an external surface (binding target), the equilibrium is altered
and the product most stabilised through surface binding is amplified
• Under optimal conditions, the desired molecule can be isolated in a high,
preparative yield
• However, this is not always the case, and there are several factors that must be
considered when designing a DCL
• All components must be completely soluble, including the products. Failure to
achieve this would cause irreversible precipitation of a product, and an inevitable
shift in dynamic equilibrium
12/3/2019Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of fulvenes and
emerging applications. Beilstein Journal of Organic Chemistry. 2019 Sep 6;15(1):2113-32.
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21. Applications
• While the reaction is reversible, the retro-DAC generally only occurs at higher
temperatures, which is not ideal. However, the combination of fulvenes and di- or
tricyanoethylenecarboxylates was found to be reversible (and dynamic) under mild
conditions at 25–50 °C
• At lower temperatures (−10 to 0 °C) the reaction was considerably slower, but
overall suggests that certain fulvene DACs can be applied in DCC
12/3/2019
Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of
fulvenes and emerging applications. Beilstein Journal of Organic Chemistry.
2019 Sep 6;15(1):2113-32.
21

22. Applications
C. Material Chemistry
• Fulvenes have been successfully used in the formation of several materials,
including dynamic polymers (dynamers), hydrogels, and precursors to charge-
transfer complexes
• Dynamers are a class of adaptive polymers formed through reversible covalent
bonds or non-covalent interactions, allowing continuous modification through bond
formation and/ or breaking
• As a result of the dynamic nature of the Diels–Alder adducts, the films were shown
to possess self-healing capabilities
• This feature allows for the incorporation of new monomers into the structure
12/3/2019
Reutenauer P, Buhler E, Boul PE, Candau SE, Lehn JM. Room
temperature dynamic polymers based on Diels–Alder chemistry.
Chemistry–A European Journal. 2009 Feb 9;15(8):1893-900.
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23. Conclusion
The interest in fulvenes due to their unique electronic properties and ability
to undergo highly selective cycloaddition reactions have fuelled advances in organic
and natural product synthesis, dynamic combinatorial chemistry and materials science,
including dynamers. The recent advances show that potential applications for fulvene
cycloaddition reactions are varied and wide in scope.

24. REFERENCES
1. Swan E, Platts K, Blencowe A. An overview of the cycloaddition chemistry of fulvenes and
emerging applications. Beilstein Journal of Organic Chemistry. 2019 Sep 6;15(1):2113-32.
2. Reutenauer P, Buhler E, Boul PE, Candau SE, Lehn JM. Room temperature dynamic
polymers based on Diels–Alder chemistry. Chemistry–A European Journal. 2009 Feb
9;15(8):1893-900
3. Billups WE, Gesenberg C, Cole R. A new methylenecyclopropene synthesis and the
isolation of a novel methylenecyclopropene dimer. Tetrahedron letters. 1997 Feb
17;38(7):1115-6.
4. Niggli U, Neuenschwander M. Fulvenes and Fulvalenes. Part 60. Does (6+ 4) Cycloaddition
Between Pentafulvene and Cyclopentadiene Take Place?. ChemInform. 1991 Mar 5;22(9)
5. Weinreb SM. Alkaloid total synthesis by intramolecular imino Diels-Alder cycloadditions.
Accounts of Chemical Research. 1985 Jan 1;18(1):16-21.
6. Moideen SV, Houghton PJ, Rock P, Croft SL, Aboagye-Nyame F. Activity of extracts and
naphthoquinones from Kigelia pinnata against Trypanosoma brucei brucei and
Trypanosoma brucei rhodesiense. Planta medica. 1999 Aug;65(06):536-40.
7. König GM, Wright AD, Angerhofer CK. Novel potent antimalarial diterpene isocyanates,
isothiocyanates, and isonitriles from the tropical marine sponge Cymbastela hooperi. The
Journal of Organic Chemistry. 1996 May 17;61(10):3259-67.
8. Siegel H. Some Preparatively Useful [4+ 2] Cycloadditions of 6, 6-Diphenylfulvene.
Synthesis. 1985;1985(08):798-801
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25. THANK YOU