Fullerenes as Photosensitizers - ACS Symposium Series (ACS

Chapter 2

Fullerenes as Photosensitizers Christopher S. Foote

Downloaded by UNIV OF ARIZONA on September 10, 2015 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0616.ch002

Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569

Photodynamic action is the action of a sensitizer, light and oxygen on biological materials. It can be mediated by electron or hydrogen-atom transfer or by singlet oxygen. Fullerenes (C and C )are excellent photosensitizers for both types of reaction, as are derivatives, dihydrofullerenes (DHFs). A DHF bound to a deoxynucleotide and hybridized to complementary DNA damages guanines near the DHF, but the reaction appears to involve electron transfer rather than singlet oxygen. 60

70

Light and oxygen are toxic to all organisms to some extent. Certain anthropogenic or naturally-occurring compounds that absorb light can "sensitize" organisms to photochemical damage by oxygen; this process is called photodynamic action.(1-3) Photodynamic damage is caused by oxidation of biological target molecules, and can lead to membrane lysis by oxidation of unsaturated fatty acids and cholesterol, enzyme deactivation by oxidation of amino acids (methionine, histidine, tryptophan, tyrosine and cyst(e)ine), and oxidative destruction of nucleic acid bases (primarily guanine). Photodynamic effects in humans include photosensitive porphyrias, drug photosensitivity, and photoallergies. Some aspects of aging of sun-exposed skin, cataract induction, and some types of photochemically induced mutations may also result from similar mechanisms.(2-4) Photodynamic sensitizers are also used in medicine: an example is the use of hematoporphyrin derivatives in tumor phototherapy, which has recently received approval for clinical use in Canada.(5J Second-generation photosensitizers such as phthalocyanines(6J or benzoporphyrins(7j that absorb in the far-red or near-infrared region are receiving increasing attention because of the ability of light of these wavelengths to penetrate tissue. Particular interest has recently been aroused in the use of photodynamic pigments as antiviral agents, for example for selective killing of HIV virus in b\ood.(8-10) Interest in photodynamic photosensitizers as pesticides and herbicides has also increased in recent years (see other papers in this volume).(4) Photodynamic Action. Photodynamic action begins when a sensitizer (Sens) absorbs light, giving an excited state (Sens*), often (but not always), the triplet. Sens* can either react directly with the substrate (Type I reaction) or with oxygen (Type II reaction).(7V,V2J The Type I reaction results in hydrogen atom or electron transfer, yielding radicals or radical ions. The Type II reaction leads mainly to singlet molecular oxygen by energy transfer. 0097-6156/95/0616-0017$12.00/0 © 1995 American Chemical Society In Light-Activated Pest Control; Heitz, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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LIGHT-ACTIVATED PEST CONTROL

Sens

hv


Radicals or Radical Ions

Type I

Type II

1 Sens*

1

Substrate or Solvent

0,

The factors that control the competition between the Type I and Type II processes are now reasonably well understood.(72,13) High oxygen concentrations favor Type II reactions, while high substrate concentrations promote Type I. In biological systems, where binding of sensitizer to substrate is common, Type I reactions are particularly favorable. Electron-rich or hydrogen-atom-donating substrates also favor Type I reactions. Sensitizer characteristics also affect the competition between Type I and Type II processes. For example, ketones favor hydrogen abstraction, while electron-poor sensitizers such as cyanoaromatics and fullerenes are particularly prone to electron transfer. Singlet oxygen can be produced in high yield in the Type II reaction by energy transfer from Sens*.(74,75,) It is an electronically excited state of oxygen, with a lifetime that varies from about 3-4 μβ in water to as long as 0.1 s in solvents with no hydrogen atoms.(75-79J In biological lipids and membranes, it probably has a lifetime considerably shorter than that in most organic solvents (50-100 ms) because of quenching by proteins and escape from the membrane into the cytosol.(20) Reactions of substrates with singlet oxygen include Diels-Alder reaction of dienes to form endoperoxides and ene reaction of alkenes to give allylic hydroperoxides. In addition, singlet oxygen reacts with electron-rich alkenes to form 1,2-dioxetanes, with sulfides to form sulfoxides (via a reactive intermediate with a S0-0 bond) and with electron-rich phenols to form hydroperoxydienones.(27 -23) H.

M

ο I

Î

R s cr

RoS

2

+

ο

HOO

\

=

Singlet oxygen emits at 1270 nm, corresponding to the energy of the singlet-totriplet oxygen transition, 22 kcal/mol.(24J This "monomol" luminescence at 1270 nm is highly forbidden, and therefore extremely weak, but can be used for direct measurement of both the absolute amount of singlet oxygen produced and its In Light-Activated Pest Control; Heitz, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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Fullerenes as Photosensitizers

lifetime.(25) This luminescence is a direct measure of the amount of singlet oxygen produced, and can lead to confident identification and quantitation. 10

3

> 0 + hv (1270 nm)

2

2

Fullerenes. We have reported the basic photophysical properties of C60 and CJO.(26,27) These studies have since been extended by many other groups.(28-33) C^Q and C both give very high yields of the triplet state on irradiation. The triplettriplet absorption spectra of C and C were measured and the extinction coefficients estimated; others have since refined them.(28-30,32,34) The energy levels of the triplets (E ) were estimated by triplet-triplet energy transfer to lie near 35 kcal/mole. The quantum yield of singlet oxygen formation is nearly quantitative for C60 and slightly lower for C . These values are also lower limits for the quantum yield of triplet. (26,27,35-37) The reduction potential of 3C Q is higher than that of the ground state by the amount of the triplet energy, (38,39) and we expected that the triplet should be reduced by electron transfer from electron donors of lower oxidation potential. Quenching of ^C^Q by electron donors occurs efficiently, by electron transfer, as shown by the production of a prominent transient with maxima at 950 and 1075 nm, which was assigned to the C^Q radical anion,(40) in good agreement with contemporary and subsequent reports(32,41-44) as well as the absorption from the donor radical cations. 7 0

6 0

7 0

T


70

6

D+ C 3

"

6 0

D- + C ^ +

6 0

In summary, COO and C70 are excellent photosensitizers in both Type II and Type I reactions. They are particularly useful in cases where unreactive substrates are to be oxidized because they quench singlet oxygen at a rate constant one to two orders of magnitude slower than dyes and porphyrins, and they do not react with it at an appreciable rate. They are also only weakly fluorescent, which makes them excellent choices for photophysical studies where small amounts of light are to be detected. Functionalization. The parent fullerenes are poorly soluble in nonpolar solvents, and not at all in polar solvents, limiting their usefulness as sensitizers in photobiology. Many groups have attached functional groups by various routes which allow greatly improved solubility in various media.(45-50j In particular, Rubin et al. recently demonstrated a simple, high-yield route to dihydrofullerenes (DHFs) via Diels-Alder addition of electron-rich dienes to C^Q.(50) This route allowed the preparation of adducts such as the one below. Dihydrofullerenes all have strong absorption throughout the visible and a weak longwavelength absorption near 700 nm. Pulsed laser irradiation of both the alcohol and the ketone gave strong transient triplet-triplet absorption spectra. Both spectra are very similar and are also similar to that of the triplet from C^Q. Both compounds gave singlet oxygen in high yields. The yield of singlet oxygen (which is a lower limit for the quantum yield of formation of the triplet) from the alcohol is 0.84 ± .04 at 532 nm and 0.72 ± 0.03 at 355 nm.(57J

As mentioned above, triplet excited C has a reduction potential near +1.6 V, and is readily photoreduced by amines and other donors to C radical anion and the 6 0

6 0

In Light-Activated Pest Control; Heitz, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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donor radical cations.(40) We expected that this reaction might lead to adducts with covalent bonds. Such adducts are formed with some amines in ground-state chemistry,(52) but the photochemical process should be more selective and easily controlled, since only one-electron reduction is possible in the photochemical process. The reduction potential of the triplet is actually high enough that electron-transfer from many donors such as electron-donor-substituted aromatics and alkenes should be possible. This should lead to adducts such as cyclobutanes or other products, depending on the reagents.

3

C

6 0

+ D-

We reacted C . Q and C70 with several different ynamines, which are excellent electron donors. Although the mechanism of the reaction is not yet certain, cyclobutenamine adducts are formed in all cases in > 50% yield.(53,54) The enamines are unique in that they also have a photosensitizer in the same molecule, and brief exposure to air and room light or chromatography in the presence of light and oxygen leads to cleavage of the enamine double bond, producing the ketoamides shown below; some of these can undergo interesting further chemical transformations.

Et

E t

R. = Alkyl, NEt , SR 2

a. Cgo, hv or standing, C HjCH ; b. ηυ, 0 , >95%; c. TsOH In C H>CH 6

3

2

6

3

We also used Diels-Alder routes to prepare derivatives in good yield.(55j OR (

'60

toluene reflux

OR

R. = Η ( 59%) R. = Me (50%)

Nucleotide linkage. A DHF-linked deoxyoligonucleotide was prepared and hybridized with a DNA strand containing a complementary sequence (see below). (56) In Light-Activated Pest Control; Heitz, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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This reaction system positions the DHF near both single and double-stranded guanosines and permits comparison of the reactivity of guanosines in these two environments. On irradiation in the presence of air, base-labile sites are created, indicating that guanosines are damaged. Only guanosines in single-stranded regions and only those directly touching or adjacent to the DHF are damaged. The residue which is not directly touching the DHF, but only two bases away is signifiicantly less affected. However, in contrast to suggestions in recent reports,(57,58) the modification does not involve 0 2 . Initial evidence suggests that DNA damage is caused by single electron-transfer between guanosine and ^C^o- This conclusion follows from the following control experiments: a) An eosin linked to the same deoxynucleotide sequence causes similar damage when hybridized and irradiated, but with different specificity (guanosines farther from the sensitizer are damaged, suggesting the intermediate is more diffusible), b) Singlet oxygen quenchers inhibit the reaction with the eosin derivative, but not the DHF. c) Carrying out the reaction in D 2 O , which promotes singlet oxygen reactions by increasing its lifetime promotes the eosin reaction but not that with the DHF, which is nearly unaffected by reagents that modify singlet oxygen lifetime.


J

cleavage sites (damage proportional to length of arrow): j

, ll

5'-AGGGTCTGCTTCAGTAAGCCAGATGCTACACAATTAGGCTTGTACATATTGTCGTTAGAACGCGGCTACAATTAATACAT-3'

Summary. These examples of functionalization suggest the rich organic chemistry of the fullerenes that is waiting to be exploited. All of the dihydrofullerene derivatives so far investigated have proven to be excellent photosensitizers, and, since their solubility properties can be controlled by suitable modifications of the functional groups, we believe they may prove to be outstanding photodynamic sensitizers. All fullerenes and dihydrofullerenes investigated share several particular advantages. All give very high yields of singlet oxygen. In addition (and in contrast to most commonly used sensitizing dyes and porphyrins), they have very low rates of quenching of singlet oxygen by the sensitizer and are also almost inert to destruction by singlet oxygen, so that they will be relatively persistent and small amounts can produce relatively large total amounts of singlet oxygen. Acknowledgments. This work was funded by NSF and NIH grants. The work was carried out by the undergraduate and graduate students and postdoctoral associates In Light-Activated Pest Control; Heitz, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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credited in the references. The deoxynucleotide work was a collaboration with groups of my colleagues, Yves Rubin and David Sigman.(56)

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Fullerenes as Photosensitizers - ACS Symposium Series (ACS

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