This PPT deals with the effect of confinement/ encapsulation of different molecules inside fullerenes such as C16, C20, C60, C70 etc. Targeted drug delivery has also been extensively discussed. This is a group PPT done by Jyoti Devi, Vikas Katoch, Zeeshan Nazir and Aryaveer Singh. Some primary data has Also been collected by the publishers to find out the threshold fullerene for encapsulation of different di-atomic molecules inside fullerenes of different size.

1. ENDOHEDRAL FULLERENES
Date: 04 July, 2022 Central
University
of Jammu
Department of Chemistry
and Chemical Sciences.
Aryaveer, Jyoti, Vikas and Zeeshan

2. Table of Contents
• Introduction
• Encapsulation of Small molecules
• Encapsulation of Metals
• Encapsulation of Biological molecules
• Silicon Fullerenes
• Computational Analysis
• References
2

3. 3
Encapsulated Small molecules
Jyoti Devi

4. Fullerenes
• Allotropes of carbon.
• The first ever fullerene was discovered by Sir Harold W. Kroto.
• Follows IPR (Isolated Pentagon Rule).
• Most popular – C60.
• sp2hybridized.
Animation reference: commons.m.Wikipedia.org 4

5. Endohedral fullerenes
Insertion or incarceration of an atom or
molecule inside a cage of carbon atoms
(fullerenes) resulting in the formation of
endohedral or encapsulated fullerenes.
5

6. Why is it done?
• Isolate different atoms or molecules
• Molecular electronics
• Nano-technology
• Targeted drug delivery
6

7. How is it done?
• Opening of Cage
• Placement of atom or molecule
• Closing of cage
Molecular
Surgery Method
7

8. Encapsulation of small molecules
Figure reference: Zhang, R.; et al. Synthesis of a distinct water dimer inside fullerene C70. Nature Chemistry. 2016, 8, 435-441.
8
Encapsulation depends majorly upon the size of the molecule and fullerene.

9. Encapsulation of
H2 molecule in C60
fullerene
Molecular
surgery method
No effect on C60 cage
due to encapsulation of
H2
High
temperature is
avoided
67% yield
produced
Reversing by
HPLC
Scheme reference: Komatsu, K.; et al. Encapsulation of molecular hydrogen in fullerene C60 by organic synthesis. Science. 2007, 307, 238-240.
9

10. 10
Endohedral Metallofullerenes
Vikas Katoch

11. 11
Endohedral Metallofullerenes
Fullerenes with metallic atoms inside their cavity are called endohedral metallofullerenes (EMFs)

12. Metal-metal bonds in EMFs
• In EMFs, the internal metal atoms always donate electrons to the fullerene cage. [1]
• Produces unique structures and fascinating electronic properties of EMFs.
• The encapsulated metal atoms can move around in fullerene cage at room temperature.
• Application in electronics, magnetism, and photovoltaics.
12

13. Encapsulation of 2 Lu atoms inside C76
• The two lutetium atoms in dimetallofullerene Lu2@C76 prefer to bind together to form
an unprecedented single metal–metal bond, in a formal valence state of [Lu2]4+@C76
4-
• HOMO-LUMO gap in [Lu2]4+@C76 (1.49eV) is close to the gap (1.71eV) calculated
at tetra-anion state. [2]
• [Lu2]4+@C76
4- [Lu2]6+@C76
6-
Correct Incorrect
13

14. Hopping of Lu2 dimer
• It has been shown that the Lu atoms can hop rapidly between six equivalent
configurations in the fullerene cage at room temperature, giving rise to a trajectory as a
tetrahedron in C76 (Td). [3]
14
Six equivalent configurations of Lu2 dimer as a tetrahedron in C76

15. Nature of bonding and Bond length
• Two-electron two-centre bond
• Back donation of negative charge from carbon cage to metal atomic orbital.
• The interaction between the encapsulated Lu2
4+ dimer and the C76
4- cage includes both
ionic and covalent ones.
• The predicted Lu-Lu bond length is 3.42 A, much shorter than the single Lu-Lu bond
length (3.82 A) in the crystals.
15

16. Stability
• Bonding energy : Strain energy (destabilizing term) and Interaction energy (stabilizing
term).
• Strain energy for Lu2 is 12.8 kcalmol-1 .
Strain energy for C76 is 52.0 kcalmol-1 .
• The interaction energy is -168.7 kcalmol-1 due to electron transfer and orbital
overlaps.
• To summarize, the bonding energy is 103.9 kcalmol-1, which is large enough to keep
Lu2@C76 (Td) stable.
16

17. Encapsulation of Biological Molecules
17
Zeeshan Nazir

18. 18
Glycine confined inside C60

19. Confined Conformers4
A B C D E
19
Molecular geometries and electronic structures were optimised using DFT (Density functional theory).

20. Variations in bond lengths (Å)4
20
Arelaxed Aconfined Brelaxed Bconfined Crelaxed Cconfined Drelaxed Dconfined Erelaxed Econfined
rN-H 1.01 0.97 1.01 1.00 1.01 1.00 1.01 0.97 1.01 1.00
rC-H 1.09 1.04 1.09 1.04 1.09 1.04 1.09 1.04 1.10 1.04
rO-H 0.98 1.01 0.97 0.96 0.98 - 0.97 0.96 0.96 0.96
rC-N 1.46 1.43 1.45 1.42 1.46 1.43 1.45 1.43 1.44 1.42
rC-C 1.53 1.40 1.52 1.39 1.53 1.43 1.51 1.39 1.53 1.39
rC=O 1.19 1.17 1.20 1.18 1.19 1.21 1.20 1.18 1.19 1.17
rC-O 1.33 1.29 1.35 1.28 1.33 1.21 1.34 1.27 1.35 1.17

21. Variations in bond angles (◦
)4
21
Arelaxed Aconfined Brelaxed Bconfined Crelaxed Cconfined Drelaxed Dconfined Erelaxed Econfined
∠HNH 107.67 109.26 105.97 106.15 107.67 111.10 108.32 109.09 105.13 103.92
∠HCH 107.21 109.26 105.67 120.92 107.21 121.46 106.79 121.05 106.23 118.69
∠NCC 111.01 88.54 118.24 89.44 111.01 88.08 109.64 85.54 114.80 90.33
∠OCO 123.61 123.48 122.76 122.37 123.61 128.26 123.19 123.33 120.87 121.38
∠HOC 105.89 96.17 106.55 103.53 105.89 - 107.03 103.16 110.33 107.62

22. Unusual behaviour of ‘C’ conformer
22
Dramatic decrease in C-O bond length (1.33 Å to 1.21 Å)
Unusual increase in OCO bond angle (123.60 to 128.260 )
Reason being: glycine (C) changes to zwitter-ion upon confinement
By proton transfer from hydroxyl towards amino group
Changing hybridisation of O-atom to SP2 from SP3
Unusual Increase in C=O bond length (1.19 Å to 1.21 Å)

23. Exohedral vs Isolated/ Relaxed
23
Aisolated AOS Bisolated BOS Cisolated COS Disolated DOS Eisolated EOS
rN-H 1.01 1.02 1.01 1.02 1.01 1.02 1.09 1.02 1.01 1.03
rC-H 1.09 1.09 1.09 1.11 1.09 1.10 0.97 1.09 1.01 1.1
rO-H 0.98 0.99 0.97 - 0.98 0.98 1.45 1.04 1.10 1.01
rC-N 1.46 1.48 1.45 1.46 1.46 1.47 1.51 1.49 0.96 1.49
rC-C 1.53 1.54 1.52 1.52 1.53 1.54 1.20 1.56 1.44 1.54
rC=O 1.19 1.21 1.20 1.21 1.19 1.44 1.34 1.22 1.53 1.22
rC-O 1.33 - 1.35 1.35 1.33 1.38 1.01 1.35 1.19 1.36
OS: Reported structure of glycine in other systems
AOS reference [5] BOS reference [5] EOS reference [7]
DOS reference
[6]
COS reference [5]

24. HB in confined AAs
24
HB possess a strong covalent character.
Serine
Glycine Alanine
While Conventional HB is of electrostatic nature.
Image references: Shahamirian, M,; Azami S.M [8]

25. Exohedral Systems
25
Targeted Drug delivery

26. Drawbacks of Conventional Medication Methods
• Poor Pharmacokinetics
• Threat of Side Effects
• Untargeted Drug Delivery / Release
26

27. C60-PEI-FA/DTX
27
Enhanced in-vivo anti-tumour effect
Enhanced pharmacokinetic effect.
Better cell apoptosis [9].
PEI: Polyethylene diamine
FA: Folic acid
DTX:Docetaxel
7.5-fold higher DTX uptake
Scheme courtesy: Shi. J, et al. [9]

28. Effect on Tumor
28
Untreated DTX C60-PEI/DTX C60-PEI-FA/DTX
After sacrificing the mice at the end of treatment of 14 days [6].
Image Courtesy: Shi, J. et al [6]

29. Some similar Conjugates
29

30. 1. C60-OH-APA-DTX. Prepared by N. Thotakura et al. [10]
30
5.8 times increase in the bioavailability of the drug.
Better cell apoptosis.
Enhanced cellular uptake.

31. 31
2. Folic Acid γ -Cyclodextrin C60. Liu et al. [11]
High aqueous solubility and pH-sensitive drug release.
Higher accumulation in tumor cells
Potent therapeutic effect and low toxicity of FA-γCD-C60

32. Silicon Fullerenes
32
Aryaveer Singh

33. 33
Fullerenes, only for Carbon

34. SILICON FULLERENE
: Stable
: Unstable
1. Encapsulation of Metals
2. Adsorption of Hydrogen On Silicon Cages
Methods to reduce
in-stability:
34

35. 1. Encapsulation of metal inside Silicon fullerene
In 2001, Kumar and Kawazoe optimized Dodecahedral Si20 Fullerene, by encapsulation of Zr atom. [12]
Fig.Shrinkage of the Si20
cage: (a) Dodecahedral Zr-encapsulated Zr@Si20
(b)–(e)optimized structures of Zr@Si20
, Zr@Si19
, Zr@Si17
, and Zr@Si16
, respectively (f) The polyhedral structure of Ti@Si16.(1)
35

36. Zr@Si16
As a result, Zr@Si16 was bonded optimized cluster.
36

37. Examples
Fig. (a)Metal encapsulated fullerene cages of Ni@Si12
,W@Si14
, and Zr@Si16
(b) The optimized structures of (from left to right) Th@Si20
fullerene, Be@Si8
cubic, W@Si12
hexagonal prism, and chair shaped Be@Si12
, respectively (1)
37

38. 2. Adsorption of Hydrogen On Silicon Cages
Fig. Optimized structures of (a) Si16ZrH8 (b) Si16ZrH8 (c) Si16ZrH16, (d) Si12H12, (e) Si16H16, and (f)
Si20H20
(1)
38

39. Effect on Silicon Fullerenes:
• Very strong bonding between M and Si atoms.
• H adsorption enhances sp3 between Silicon atoms.
• The High HOMO-LUMO gap.
OVERALL ENERGY
DECREASED AND
STABILITY
INCREASED
39

40. What we have done
Table reference://nanotube.msu.edu/fullerene/
Different fullerenes on the basis of size.
40

41. 1.Threshold fullerene for H2(C20).
Equilibrium structure of H2@C20 computed at B3LYP/6-31g(d,p) level of theory.
2.Threshold fullerene for N
2
(C
28
).
Equilibrium structure of N2@C28using B3LYP/6-31g(d,p) level of theory.
41

42. 3. Threshold fullerene for O2(C28).
Equilibrium structure O2@C28 optimized using B3LYP/6-31g(d) level of theory
4. Threshold fullerene for F2(C32).
Equilibrium structure of F2@C32 using B3LYP/6-31g(d,p) level of theory.

43. References
1. Kobayashi, K. et al.,Endohedral dimetallofullerenes Sc2@C84 and La2@C80. Are the metal atoms still inside the fullerence
cages?,Chemical Physics Letter. 1996, 246, 502-506.
2. Takeshi A; et al. 13C and 139La NMR Studies of La2@C80: First Evidence for Circular Motion of Metal Atoms in Endohedral
Dimetallofullerenes. Communications. 2008, 36, 1643–1645.
3. Yamada, M. et al. Synthesis and characterization of the D5h isomer of the endohedral dimetallofullerene Ce2@C80: two-
dimensional circulation of encapsulated metal atoms inside a fullerene cage. Chemistry Europe. 2009, 21, 9486-93.
4. Shahamirian, M.; Azami, S.M.; Encapsulation of glycine inside C60 fullerene: Impact of confinement. Physics Letters A. 2019,
383, 126004.
5. Hang Hu, Y.; Ruckenstein, E. Complexes of a bio-molecule and a C60 cage, J. Mol. Struct., Theochem. 2008, 850, 67–71.
6. Leon, A.; Jalbout, A.F.; Basiuk, V.A. Fullerene–amino acid interactions. A theoretical study, Chem. Phys. Lett. 2008, 452, 306–
314.
7. Leon, A.; Jalbout, A.F.; Basiuk, V.A. SWNT–amino acid interactions: a theoretical study, Chem. Phys. Lett. 2008, 457, 185–190.
8. Shahamirian, M,; Azami S.M.; Strong intramolecular hydrogen bonding in confined amino acids. Journal of Molecular Graphics
and Modelling. 2021, 106, 107913.
43

44. 9. Shi, J. et al. PEI-derivatized fullerene drug delivery using folate as a homing device targeting to tumor. Biomaterials. 2013, 34,
251-261.
10. Thotakura, N. et al. Aspartic acid derivatized hydroxylated fullerenes as drug delivery vehicles for docetaxel: an explorative
study. Artificial cells, nano medicine, and biotechnology. 2017, 46, 1763-1772.
11. Liu et al. Folic Acid Functionalized γ-Cyclodextrin C60, A Novel Vehicle for Tumor-Targeted Drug Delivery. J. Biomed.
Nanotechnol. 2016, 12, 1393–1403.
12. Kumar, V. Metal Encapsulated Clusters of Silicon: Silicon Fullerenes and other Polyhedral forms. Challenges and Advances in
Computational Chemistry and Physics. 2008, 24, 114-14.
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45. Thank you so much!
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