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19Porphyrins Пофирины
Макрогэтэроцмклы
http://macroheterocycles.isuct.ru
Review Обзор
DOI: 10.6060/mhc180690l
Advances in the Synthesis of Porphyrin-Fullerenes
Viktoriya S. Lebedeva,a@ Nadezhda A. Mironova,a Ramzes D. Ruziev,b and Andrey F. Mironov a
aMIREA-Russian Technological University, 119454 Moscow, Russian Federation bScientific Centre for Expert Evaluation of Medicinal Products, 127051 Moscow, Russian Federation @Corresponding author E-mail: [email protected]
The review focuses current research in the synthesis, properties, and potential applications of covalently linked porphyrin- and chlorin-fullerenes. An overview of the most popular methods to prepare porphyrin- and chlorin-C60 fullerene conjugates is given.
Keywords: Porphyrins, fullerenes, photoinduced electron transfer, photosensitizers, photodynamic therapy.
Достижения в синтезе порфирин-фуллеренов
В. С. Лебедева,а@ Н. А. Миронова,1 Р. Д. Рузиев,ь А. Ф. Миронов1
аМИРЭА - Российский технологический университет, 119454 Москва, Российская Федерация ьНаучный центр экспертизы средств медицинского применения, 127051 Москва, Российская Федерация ®Е-таИ: [email protected]
Обзор посвящен текущим исследованиям в области синтеза, свойств и потенциальных применений ковалентно связанных порфирин- и хлорин-фуллеренов. Дается обзор наиболее популярных методов получения конъюгатов порфирин- и хлорин-С60 фуллерена.
Ключевые слова: Порфирины, фуллерены, фотоиндуцированный перенос электрона, фотосенсибилизаторы, фотодинамическая терапия.
Introduction
Unique electronic and photophysical features of porphyrins and fullerenes lead to great interest in creation of hybrid structures based on them. Porphyrin macrocycle, its di- and tetrahydro derivatives absorb light at wide range between UV and near IR-region, which allows to use similar compounds as light-absorbing antennas. Porphyrins are the basis of pigments, participating in natural photosynthesis, they being quite stable and being able to undergo various chemical functionalization pathways. They possess small HOMO-LUMO gap, which makes them very redox active, and the introduction of different metals into their macrocycle alters their redox potentials.[1] Fullerenes, in contrast to porphyrins, absorb visible light weakly, they being excellent electron-acceptors. Fullerene C60, similarly to quinones, the naturally occurring electron acceptors,
is readily reduced to form stable radical pairs when coupled to a donor.[2] Besides, C60 has small reorganization energy resulting from its rigid spherical shape and n-system delocalization.[3,4] Under irradiation of porphyrin-fullerene structures after the excitation of porphyrin macrocycle either energy transfer with the fullerene activation either electron transfer to fullerene takes place, the ion-radical pair being formed. The combination of porphyrins and C60 in the donor-acceptor systems allows to obtain a long-living charge-separated states as the speed of charge recombination is substantially lower than the speed of charge separation.[5] There have been published a considerable number of papers on molecular photosystems based on porphyrins and fullerenes synthesis (beginning with simple donor-acceptor dyads till multichromophoric systems), as well as on supramolecular structures using different kinds of non-covalent interactions (hydrogen bonds, anion
binding, metal-ligand coordination, crown ether-ammonium cation binding, electrostatic interactions and n-n-stacking) in order to simulate natural photosynthetic systems and to study the basic principles of the photoinduced energy and electron transfer in antenna-reaction centers, as well as with the aim of creation of artificial storage and energy transfer systems.[6-18] For a number of the cova-lent-bound porphyrin-fullerene systems the charge-separation lifetime was comparable and even exceeded the lifetime of the charge-separated state in the natural bacterial photosynthetic reactive center.
The photodynamic activity of porphyrin- and chlorin-fullerenes is also studied with the aim to create novel efficient photosensitizers for the photodynamic therapy of cancer and antimicrobial photodynamic inactivation. When photoinduced, fullerenes transform into the triplet state almost in 100 % quantum yield and then generate efficiently the singlet oxygen or superoxide anion - radical and other active radicals, giving rise to destruction of tumor cells and microorganisms.[19-22] Thus, the two types of effects during the PDT, in which the acting agents are favorably either superoxide radicals or singlet oxygen for the fullerenes coexist. In this connection they can be more efficient when carrying out the PDT under the cancer hypoxia conditions. Fullerene, however, absorb poorly in the visible and IR regions of spectrum, which are the most convenient for using in PDT. In this connection the combination of fullerene with porphyrins and chlorins, which absorb light intensively in this region and transfer the excitation energy or electron to fullerene allow to solve this problem.
Several methods to prepare covalently linked porphyrin- and chlorin-fullerenes are known.
1. The Methods of Porphyrin-Fullerene Conjugates Production
Among the fullerene modification methods known[23-26] for the porphyrin- and chlorin-fullerene synthesis the following methods are used most often: the Bingel reaction, C60 condensation with butadienes and the Prato reaction. The first technique is based on the condensation of porphyrins, containing the residue of malonic ester, with C60 effected by treatment with iodine in the presence of bases (the Bingel reaction) (Scheme 1).
The second technique is the condensation of porphyrins, containing the butadiene residue, with C60: the successive conducting of enyne metathesis and the Diels-Alder reaction. The terminal alkyne interacts with olefin in the presence of the Grubbs catalyst and the substituted butadiene being formed condenses with C60 when heated (Scheme 2).
1,3-Dipolar cycloaddition of ylide being formed as a result of condensation of ^-methylglycine (sarcosine) with formyl-containing porphyrin to fullerene is the basis of the third method - the Prato reaction (Scheme 3).
The last approach is widely used in the synthesis of porphyrin-fullerenes. The intermediate azomethine ylide being formed in the course of the reaction reacts with the C60 double bonds yielding pyrrolidine-fullerene (Scheme 4). The pyrrolidine cycle formed binds between the two 6-membered fullerene cycles.
Scheme 1. C60 conjugates synthesis using the malonic acid derivatives.
H
HOOC-
Me
+
RCHO R = porphyrin
toluene, reflux Me—N
Scheme 3. The Prato method.
тт^^^ H toluene, reflux
H°°C N^ + R—CHO ^^ Me
-CO2 -H2O
R = porphyrin
Me
N
CH2
R
Me—N
toluene, reflux Ar
Scheme 4. The Prato reaction mechanism.
C
60
R
The application of some other ^-substituted glycines instead of ^-methylglycine promotes the administration of two different substituents into the pyrrolidine ring.[27-31] Great excess of amino acid and aldehyde may result in the formation of fullerene with 2, 3 and more pyrrolidine moieties.
Lately the substantial modification of the Prato method was proposed, based on cycloaddition of nitryl oxide at the fullerene double bond in the presence of diacetoxyiodo-benzene (Scheme 5).[32] The condensation involved in contrast to the Prato reaction proceeds under mild conditions with notably high yields. The isoxazoline cycle produced
may possess different substituents at the position 3. Such fullerene derivatives are shown to be efficient electron acceptors.
The arylation of hexa-chlorin substituted fullerene C60Cl6 according Friedel-Crafts by phenylacetic and benzylmalonic acids with the production of C60(Ar)5Cl is a suitable approach to the production of water-soluble fullerene derivatives (Scheme 6). C60Cl6 is synthesized preliminary by interaction of C60 and ICl in 1,2-dichlor-benzene at 40 °C under the pressure ~1 mbar.[33] Complex ethers groups saponification leads to the formation of C60 derivatives with 5 and 10 carboxy groups. The condensation
.Ph
I
H
R = porphyrin
Scheme 5. Synthesis of C60 conjugates using nitrile oxides.
R-C=NQ)
R—C=N-0
■"60 .
CI
CF3COOH-CH3COOH- I R1 _ HCl-H2O-PhCl 1—- R1 _
HOOC
R! _ COOMe, CH(COOMe)2 R! _ COOH, CH(COOH)2
KOOC
HOOC
HOOC
conhr2
COOH
COOK
R2 = chlorin
Scheme 6. Synthesis of C derivatives with 5 and 10 carboxy groups and water-soluble chlorin-C„
R
R
of chlorins containing amino group with such derivatives promotes the production of conjugates which are highly soluble in water.[34]
2. Donor-Acceptor Porphyrin- and Chlorin-Fullerene Systems
Considerable number of various dyads, triads and multi-chromaphoric compounds was synthesized and it was shown that energy or electron transfer occurs in them when photoexcited. The photoinduced electron transfer from the excited singlet state of porphyrin or chlorin donor to fullerene results in the formation of a system with separated charges, its lifetime depending on energy of this
state, the type of a linker between the donor and acceptor molecules as well as on the nature of solvent.
Models based on porphyrin- and chlorin-fullerenes are created to study the photosynthesis mechanism and to create artificial solar energy converters.
2.1. Dyads of Porphyrins and Chlorins with C60 Fullerene
The first porphyrin-fullerene dyad - porphyrin zinc complex - C60 2 described in literature was synthesized by the interaction of diene-substituted porphyrin 1 and C60 according to the Diels-Alder reaction (Scheme 7).[35] The time-resolved fluorescence spectroscopy demonstrated that
Scheme 7. Synthesis of dyad 2 by the Diels-Alder method.
2
1
iii
Scheme 8. Synthesis of zinc chlorin-C60 dyad with a rigid spacer. Reagents and conditions: i - LiAlH4, THF, 35 °C; ii - o-O2NPhSeCN, nBu3P, 55 °C (a), H2O2, THF (b); iii - C60, toluene, reflux..
when the dyad is photoexcited in toluene and benzonitrile the charge-separated state ZnP'+-C60'_ is generated as a result of the electron transfer from porphyrin to fullerene with the rate constant &CS=10U s-1.
The dyad based on synthetic chlorin and fullerene C60 6 with a rigid spacer was synthesized using the Diels-Alder reaction to minimize electronic interaction between donor and acceptor (Scheme 8).[36] The preformed initial zinc chlorin 3 was turned into diol 4, and subsequently into diene 5. Zinc chlorin-C60 dyad was synthesized by boiling the latter with C60 in toluene for further investigation of the donor-acceptor distance impact to the characteristics of the molecular dyads.
The substituted butadienes were also used in the synthesis of C60 conjugate with chlorinp6 cycloimide.[37] The initial purpurin 18 (7) reacted with propargylamine in toluene at 80 oC forming ethinylcycloimide 8 with 80 % yield (Scheme 9), its treatment with ethylene in the presence of the Grubbs catalyst affording the compound 9 with 40 % yield. The conjugate 10a (30 % yield) was obtained by heating diene 9 with C60 in toluene. To study the electron transfer, the dyad 10a was transformed into zinc complex 10b. The emission intensity of the chlorin component in the fluorescence spectra of the conjugates 10a and 10b was noticeably less than that of the initial chlorin, demonstrating an efficient electron
transfer towards C .
60
Fullerene C60 nucleophilic cyclopropanation using malonic acid substituted derivatives is one of the widespread
approaches to the porphyrin - C 60 conjugates production.138"421 The conjugates 11 and 12 were prepared according to this technique (Figure 1).[38,39] Zinc porphyrin in the conjugate 11 is rigidly connected at the two opposite sites with C60. In the conjugate 12 porphyrin is attached only at one site of the fullerene.[39] Despite these differences, photophysical and electrochemical features of the compounds 11 and 12 were similar, showing, in the authors' opinion, the significant contribution of non-covalent interactions between zinc porphyrin and fullerene to the general distribution of electron density.
Porphyrin-fullerene dyads with chromophores' location "face-to-face" were synthesized via the Bingel reaction of cyclopropanation 13-16 (Figure 2).[43-47] For the compounds 13-16, as well as in the cases of other dyads, porphyrin's fluorescence in the photoinduced excited state is almost quenching due to the energy or electron transfer from the excited singlet state of porphyrin to fullerene.
Thorough photophysical examinations of the compounds synthesized 13-16 demonstrated that, as contrasted to the other porphyrin-C60 dyads generating the charge-separated state only in the polar solvents, ZnPM"-C60'_ charge-separated state is produced both in polar and nonpolar solvents under photoexcitation of the systems 13-16 the lifetime of the charge-separated state in the polar solvents decreasing significantly.[43-46]
A water-soluble dyad Zn-TPP-C60 17 containing dendron Newkome was synthesized by the authors (Fig-
H,
Me"""
MeOOC
O O 7
H
Me""""
MeOOC
H
Me"'"
MeOOC
v /
H Z^N HN-
Me" ^
MeOOC
10a,b
M = 2H(a), Zn(b)
Scheme 9. Synthesis of chlorin-C conjugates 10a,b. Reagents: i - propargylamine; ii - H2C=CH2; iii - C (a), Zn(OAc)2 (b).
,Ph
11
12
Figure 1. Structures of porphyrin-fullerenes with cyclopropane bridges.
14 M = 2H
15 M = Zn
16
Figure 2. Structures of porphyrin-C dyads with chromophore's location "face-to-face"
HO
OH
O OH
OH
OH
l oh
HO /^OH
O
17
Figure 3. Structure of water soluble Zn-TPP-C dyad.
ure 3).[48] However, the pronounced hydrophilic moiety along with the hydrophobic porphyrin-fullerene segment present in this aggregate resulted in the formation of micellar aggregates in water and precluded the charge distribution studies.
Cyclopropanation using the malonic acid derivatives enabled more complicated adducts of fullerene C60 to be obtained.[49] The reaction conditions allowing to synthesize fullerene both with 1 and 6 malonate molecules were worked out. The proposed multi-attachment terms were applied
for hexa-substituted fullerene synthesis with one residue of porphyrin 20a,b (Scheme 10). The initial porphyrin 18 was condensed with C60 via the Bingel method and the dyad obtained 19 was treated with ferrocenylmalonate to form hexa-adduct 20a (30 % yield), which was successively turned to zinc complex 20b.[49]
The attachment of several malonic ester moieties disturbs significantly the conjugation of n-electronic fullerene system and reduces its electrophilic characteristics, result-
ing in the photoinduced transfer lesion. In this connection the bis-pyropheophorbide a and fullerene - C60 conjugate 21 (Figure 4) obtained by the authors,[50] modified with 5 moieties of malonic ester, can be regarded not as a donor-acceptor system but merely as a carrier for drug delivery.
Using the formyl-substituted meso-arylporphyrins presents one of the applications of the Prato reaction for the fullerene-porphyrin conjugate synthesis in which porphyrin and fullerene are bound via pyrrole linkers.
Ph
-NH Na Ph^\ }— Ph
Ph
\ \
/
N HN
O
18
YY
OO
O
Ph
m O.
19
M = 2H(a), Zn (b)
O
R
O
=A
R
20a,b
Fe
O
O
Scheme 10. Synthesis of porphyrin - C60 conjugate with 12 ferrocene moieties. Reagents and conditions: i - I2, DBU, C60, toluene; ii -DMA, DBU, CBr4, CH2R2, toluene (a); Zn(OAc)2, THF, reflux (b).
R^ F"R
R R
Figure 4. Structure of bis-pyropheophorbide a - C60 conjugate. Макрогетероцикnbl /Macroheterocycles 2018 11 (4) 339-362
Me I
N
22a,b
M = Mg (a), Zn (b)
Figure 5. Structure of donor-acceptor systems with a flexible linker 22a and 22b.
Dyads 22a,b (Figure 5), containing magnesium and zinc porphyrins were produced in such a way, the central metal ion influence on the photoinduced charges' separation and their recombination was studied.[51,52] The initial 5-(4'-hydroxyphenyl)-10,15,20-triphenylporphyrin was treated with 4-bromoetoxybenzaldehyde in the presence of K2CO3 to synthesize the corresponding porphyrin-fullerene with a flexible linker and the formyl-containing derivative obtained was condensed with Ж-methylglycine and C60 to give porphyrin-fullerene 22.
In the course of study of the metal complexes obtained the electron transfer from porphyrin to fullerene was shown to yield the charge-separated state МР'+-С60'_. Efficient quenching of the excited singlet state ZnP and MgP
was revealed. The electron transfer to C at the rate con-
60
stant of 2.2-109 s-1 occurred when quenching the ZnP singlet state,[36] with the MgP singlet state quenching including energy transfer to C60 and generating the excited singlet state C60 with subsequent charge separation (the rate constant was 1.7-109 s-1).[52] The rate constant of charge recombination
(lifetime of the charge-separated state) for the compound 22a was 1.8-106 s-1 (560 ns) and for the compound 22b -3.3-106 s-1 (300 ns).
The preparation of the porphyrin - fullerene dyad 27 (ZnImP-C60) (Scheme 11) with a short linker allowed to prolong the charge-separated state lifetime up to 310 ^s in ben-zonitrile at 278 K.[53] The corresponding formyl porphyrin 24 was produced by condensation of porphyrin-2,3-dion 23 with arylaldehyde in the presence of NH4OAc when boiled in the mixture AcOH-CHCl3 (1:1), it being transformed into metal complex 25. The Prato reaction was used for the porphyrin-fullerene 27 production. The dyad's yield was 46 %.
The presence of the photoinduced electron transfer for the dyad ZnImP-C60 27 was confirmed by the picosecond time-resolved absorption spectrum.
The rate constant of electron transfer from 'ZnImP* to C„
60
was 1.6-106 s-1. According to the authors, the charge-separated state was notfoundforthe dyad containingfree-base porphyrin
H2Imp-C60 26.
Scheme 11. Synthesis of porphyrin - fullerene dyad 27. Reagents and conditions: i - arylaldehyde, NH4OAc, AcOH/CHCl3; ii - Zn(OAc)2; iii - V-methylglycine, C60, toluene, reflux.
The dyad chlorin-fullerene 30 was synthesized using the Prato reaction.[54] Chlorin-fullerene 29a was obtained by heating 3-formylcycloimide 28 with V-methylglycine and C60 (Scheme 12), its treatment with zinc acetate giving metal complex 29b.
Zinc complex of the chlorin-fullerene dyad 29b generates extremely long-lived charge-separated state Zn-Chl'+ -C60'_ with sufficiently high quantum yield (the lifetime is 230 ms at 25 °C and 120 s at -150 °C, the quantum yield of the charge-separated state is 12 %).
It's interesting to note that even slightly less close contact between C60 and chlorin macrocycle in dyad 30 results
in the reduction of the charge-separated state lifetime to 110 ms (Figure 6) (at 25 °C).[55]
2.2. Triads, Tetrads, Pentads, Hexads, Containing Porphyrins and Fullerene C60
The triad 31 was constructed using the concept of multistep electron transfer in the natural photosynthesis (Figure 7).[56] The structure involved consisted of diaryl-porphyrin, carotenoid polyene and fullerene. In this system porphyrin is the initial donor of energy or electron, carotenoid being a secondary electron donor, fullerene acting
OHC
\
H-
ме
MeO2C
(CH2)sMe
28
Me
H
ме"
MeO2C
(CH2)sMe
•• I--
29a M = 2H -29b M = Zn
Scheme 12. Synthesis of chlorin-fullerene C60 dyad 29a and its metal complex 29b. Reagents and conditions: i - V-methylglycine, C60, toluene, reflux; ii - Zn(OAc)2/MeOH.
H
Me**
MeO2C
Me^ 7 ^fV-Et N _.N=
\ X /
-N N-^ -J /-Me
Figure 6. Structure of chlorin-fullerene 30.
as an acceptor. This construction was supposed to allow reducing the charge recombination speed and increasing the charge-separated state lifetime.
Formyl-containing porphyrin derivative was synthesized preliminarily to obtain the triad 31. To achieve this the initial 5-(4-aminophenyl)-15-(4-methoxycarbonyl) phenyl-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphy rin was turned into a corresponding benzyloxycarbonyl derivative. The ester was reduced with lithium aluminum hydride and the alcohol formed was oxidized by manganese dioxide. The formylporphyrin obtained interacted with sarcosine and C60 to form porphyrin-fullerene. The triad 31 was obtained after its treatment with boron tribromide and carotene acid chloride.
Figure 7. Structure of porphyrin-carotenoid polyene-C60 triad 31. Макрогетероциклы /Macroheterocycles 2018 11 (4) 339-362
Photoexciting the triad 31, electron transfer from porphyrin to fullerene occurred in 2-methyltetrahydro-furan, with an intermediate charge-separated state being formed (C-H2P'+-C60'-), and further hole transfer from porphyrin to carotenoid, charge-separated state being formed (C"+-H2P-C60"-) with a quantum yield 0.14.[56] Charge-separated state lifetimes were 170 ns (in a solution) and 1.5 ^s (in a glass matrix at 77 K). However the authors noted that the quantum yield of the long-lived charge-separated state in the triad 31 (C'+-H2P-C60'-) still concedes to the analogous characteristics in the natural photosynthesizing reaction center.
The triad zinc porphyrin-free-base porphyrin-fullerene 39 was synthesized applying the same concept of the multistep electron transfer (Scheme 13).[57] Synthetic intermediate 33 was obtained by the condensation of dipyrrolylmeth-ane with 3,5-di-fer/-butylbenzaldehyde in the presence of BF3-OEt2 and subsequent alkali hydrolysis of the compound 32 (Scheme 13). The incorporation of zinc atom into diporphyrin and the protection of the latter against demetal-
lation appeared to be an important step in the ZnP-H2P-C60 synthesis, subsequent synthesis stages being carried out under neutral or alkaline conditions. Porphyrin diacid 33 was being transformed into the corresponding bis-acid chloride 34. The cross-condensation of zinc porphyrin 35, diacid chloride 34 and 4-tert-butyldimethylsilyloxymethylaniline in benzene in the presence of pyridine yielded porphyrin mixture. Diporphyrin 36 was isolated (in 34 % yield) after the chromatographic separation of the latter. Compound 37 resulted from the elimination of the tert-butyldimethylsilyl group in the compound 36 by treatment with «-Bu4NF, it being oxidized with manganese dioxide to form the derivative 38. ZnP-H2P-C60 39 was synthesized by the Prato reaction via the interaction of the compound 38, V-methylglycine and C60 in toluene with 79 % yield.
The charge-separated state ZnP'+-H2P-C60'- was generated under the triad 39 photoexcitation resulting from the electron transfer towards fullerene (quantum yield 0.4 and lifetime 21 ^s).[57]
vi
Ar Ar
Ar = 3,5-di-ferf-butvlphenvl
Scheme 13. Synthesis of triad 39. Reagents and conditions: i - KOH, THF, EtOH; ii - SOCl2, pyridine; iii - NH2C6H4CH2OSi(Me)2CMe, pyridine, benzene; iv - Bu4NF; v - MnO2; vi -V-methylglicine, C60, toluene, reflux.
The authors[58] introduced ferrocene (Fc) into the triad structure 39 as the third electron donor and synthesized the tetrad Fc-ZnP-H 2P-C60 40 (Figure 8). One could observe the energy transfer from zinc porphyrin singlet-excited state to the free-base porphyrin, and then the electron transfer from the porphyrin singlet-excited state to fullerene, primary charge-separated state (Fc-ZnP-H2PM"-C60'_), the hole migration from H2P'+ to ZnP giving an intermediate charge-separated state (Fc-ZnP'+-H2P-C60'~), the hole migration from ZnP*+ to Fc yielding long-lived charge-separated state (Fc +-ZnP-H2P-C60'-) with a lifetime of 380 ms (benzonitrile, 193 K), which is significantly larger than the initial triad charge-separated state lifetime (21 ^s). Such a long-lived charge-separated state is comparable with the processes proceeding in the bacterial photosynthetic reaction center.
To increase the light harvesting efficiency and charge separation pentad Fc-(ZnP)3-C60 41 was constructed (Figure 9), its three molecules of zinc porphyrin serving as light harvesting chromophores.[59] The final charge-separated state Fc+-(ZnP)3-C60'- in this case had the lifetime of 0.53 s in dimethylformamide at 163 K and relatively high charge separation efficiency in benzonitrile (the quantum yield 0.83).
The authors[60] succeeded in achieving a long charge-separated state lifetime, having synthesized the triad Fc-ZnP-C60 45 (Scheme 14). The electron donor ferrocene and the acceptor C60 in this triad are linked through imidazole rings located at the opposite p,p'-pyrrole sites of zinc
porphyrin macrocycle. The compound 44 was produced due to the interaction of tetraone 42[61] with ferrocene-carboxaldehyde in the presence of ammonium acetate upon boiling in the mixture CHCl3-AcOH (5:1) with subsequent condensation of the dion formed 43 with terephthaldehyde and Zn(II) introduction. The condensation with fullerene C60 gave a triad 45 with 73 % yield. The study of photophysi-cal properties of the structure obtained demonstrated that the electron transfer to C60 results from porphyrin excitation with the subsequent hole transfer to ferrocene forming long-lived charge-separated state, its lifetime being 630 ^s (benzonitrile, 20 °C). The electron transfer rate constant amounted to 4.3-109 s-1. The charge-separated state production Fc+-ZnP-C60'- was verified by nanosecond laser flash photolysis technique.
The development of antenna molecular systems with non-linear chromophore arrangement provides the excitation energy transfer to the reaction center of several peripheric chromophores at once.[62,63] The pentad (ZnP)3-H2P-C60 46 is one of the examples of such an approach (Figure 10). The charge-separated state lifetime for this system amounted to 460 ns in the viscous agar medium. The necessity to use the viscous medium resulted from the presence of ester bonds between the structural compounds in the molecule 46. The presence of flexible linkers resulted in undesirable electronic interactions and the charge-separated state lifetime reduction.
Ar
Ar
CH3 I 3
Ar ■NH N" N HN"
Ar = 3,5-di-tert-butylphenyl Ar
O
■c—N
42
Ar
Fe
CH3 I 3
.Nv
43
Figure 8. Structures of ZnP-H2P-C60 triad 39 and Fc-ZnP-H2P-C60 tetrad 40.
O
II H C—N
Fe
CH3 I 3
N
Figure 9. Structure of Fc-(ZnP)3-C60 pentad. Макрогетер0циmbl /Macroheterocycles 2018 11 (4) 339-362
Ar4 J~\ yAr
O
42
i
Fe
O
43
ii
44
Fe I
H ^vO
N. ^N
Me
I
N
Ar = 3,5-di-iert-butylphenyl
Scheme 14. Synthesis of Fc-ZnP-C60 triad 45. Reagents and conditions: i - ferrocenecarboxaldehyde, NH4OAc, CHCl3-AcOH (5:1), reflux; ii - Zn(OAc)2, CH2Cl2-MeOH (3:1), reflux (a), terephthalaldehyde, NH4OAc, CHCl3-AcOH (5:1), reflux (b); iii - V-methylglycine, C60, toluene, reflux.
To synthesize the porphyrin tetrad 47 (Figure 11) the Sonogashira reaction was implemented. The coper-free reaction conditions were selected, which allowed to avoid the metalloporphyrins formation. The tetrad 47 was brought about, the yield being 67 %. It was further transformed into a corresponding alcohol for the subsequent malonic acid attachment.
The pentads 48-51 were prepared by the author,[64] containing alkyl substituents of different lengths, as well as dendron Newcome of the first and second generations (Figures 12 and 13). Zinc porphyrins in the compounds obtained acted as efficient electron donors, and the central porphyrin molecule acted as a secondary electron donor for C60. Rigid binding of porphyrins by means of triple bonds was imple-
mented to prolong the charge-separated state lifetime. Additional substituents were introduced to improve solubility in different media, as well as inhibition of the intramolecular interactions between porphyrins and C60.
Pentads containing dendrons moieties 50 and 51 were successfully prepared through the interaction between the synthesized porphyrin-malonate with C60 under the Bin-gel-Hirsh reaction conditions. The hydrolysis of tert-butyl ester groups was carried out by treatment of the compounds 50a and 51a TMSOTf in 2,6-lutidine.
The photophysical characteristics of the pentads 48, 49 and 51a were studied. The electron transfer occurred in the systems involved under photoexcitation in the Soret band region, forming the charge-separated state (ZnP)3-H2P'+-C60\ The solvent's nature was shown to play an important role in this process. The electron transfer in benzonitrile proceeded in less than 10 ps, while in toluene in 70-100 ps. The structure of side substituents doesn't influence significantly the charge separation process.
The molecular system 54 was designed to reduce the charge recombination rate.[65] The previously described tetrad 52 was applied as an initial compound in its synthesis (Figure 14). [6365] The pentad 53 resulted from the palladium catalyzed interaction of the compound 52 with 5-(4-formylphenyl)-15-(4-iodinephenyl)-10,20-dimethyl-porphyrin, the compound 54 resulting from the pentad 53 under the Prato reaction conditions.
It was stated that under the photoexcitation conditions of the compound 54 in 2-methyltetrahydrofuran the electron transfer occurs from the singlet excited state H2P towards C60, generating charge-separated state (ZnP)3-H2P*+-C60"\ its lifetime being 25 ps, quantum yield being 0.98.[65] The subsequent positive charge migration occurs from H2P*+ to ZnP, producing the final charge-separated state (ZnP)3*+ -H2P-C60\ its lifetime being 240 ns, which is 100 times the lifetime of the primary charge-separated state.
The pentad 59 consisting of three BODIPY (BDP) fragments (antenna), zinc porphyrin (energy acceptor and electron donor) and C60 (electron acceptor) is the example of another similar complex (Scheme 15).[66,67]
The metal complex 55 was synthesized beforehand,[68] then it was treated with 1,3 -dibromopropane and 4-hydroxy-benzaldehyde in the presence of K2CO3 in DMF to form bromide 56 and aldehyde 57. The porphyrin-fullerene 58 was synthesized by the interaction of the derivative 57 with Ж-methylglycine and C60 via the Prato reaction.
Click-reaction was applied at the final step of the synthesis - Cu(I)-catalized 1,3-dipolar cycloaddition between the azides and alkynes. The alkyne-containing porphyrin-fullerene 58 interacted with azide-BDP in the presence of sodium ascorbate and CuSO45H2O forming the pentad (BDP)3-ZnP-C60 59 with 88 % yield.
The compound 59 absorbs in a wide range of wavelengths (from 300 to 700 nm). Overlapping of the emission spectra of BODIPY and the absorption of ZnP leads to energy transfer from the singlet-excited state of BODIPY to ZnP with a sufficiently large rate constant of 2.7-1010 s-1. The further electron transfer from ZnP to C60 resulted in charge-separated state (BDP)3-ZnP4"-C60'_ with the rate constant being 1.7-1011 s-1, the charge recombination rate constant
Figure 10. Structure of (ZnP)3-H2P-C60 pentad 46.
amounting to 1.0-109 s-1, the lifetime of charge-separated state being 1 ns.
The structure consisting of two triphenylamide moieties (antenna and electron donor), porphyrin (energy acceptor and electron donor) and C60 (acceptor) serves as another example of multistep electron transfer (Scheme 16).[69]
Dipyrromethane 63 was condensed with 4-(diphenyl-amino)benzaldehyde 64 in the presence of BF3-OEt2 with subsequent oxidation with /-chloranil. Having neutralized the reaction mixture with triethylamine the product 62 was hydrolyzed under alkaline conditions to form 5,15-di(/-carboxyphenyl)-10,20-di(triphenylamine)porphyrin 63. The compound 63 was turned into acid chloride, which interacted with formyl-substituted aniline and then with 4-ferro-cenylaniline to produce the porphyrin 64. The latter reacted with ^-methylglycine and C60, zinc was incorporated into the polyad produced 65a (the compound 65b).
The singlet-singlet energy transfer from triphe-nylamine to ZnP and the electron transfer from ZnP to C60 was observed when the polyad 65b was illuminated in the ultraviolet region of spectrum. In this transition state Fc-ZnP(TPA)2'f-C60'- the hole transfer from ZnP to Fc occurs to form the final charge-separated state Fc-ZnP(TPA) 2*+-C60'-, its lifetime being 8.5 ^s,[69] which is much greater than that for ZnP(TPA)3-C60 66[70] (Figure 15).
The Prato reaction was also used when producing the photoconductive nanostructures based on amphiphilic chiral dyad 67, being photoinduced by light in the visible spectrum region (Figure 16).[71] The dyad 67 was synthesized [3+2] by cycloaddition of porphyrin, containing azide group in the meso-phenyl substituent and alkyl-functionalized fullerene C60. The compound 67 self-assembles into nanofib-ers and presents a significant interest for photovoltaics.
Some other amphiphilic dyads 68 and 69 were obtained by the authors,[72] having analogous hydrophilic moiety with triethylene glycol residues, but different linkers between porphyrin and fullerene, self-assembling into nanotubes of varying spacial and geometric structure. The nanotubes, formed by the dyad 68 with an ester bond, had a bi-layer wall with coaxially generated along the tube's axis donor and acceptor domains and possessed a significant photoconductivity. Using the methods of scanning and transmission electronic micrographics it was stated that the nanotubes (diameter 32 nm and wall thickness 5.5 nm) result from self-assembling of the dyad 68. On the contrary, the dyad 69 with a rigid arylacetylene linker due to self-assembling resulted in nanotubes with a monolayer wall and less regular geometry of the donor and acceptor stacking, bringing about the weakening of photoconductivity.
Ov
O
O
O—
O
O
Figure 11. Structure of tetrad 47.
3. Porphyrin- and Chlorin-Fullerenes and PDT
The creation of hybrid structures based on porphyrins and chlorins, absorbing intensively in the range of visible spectrum, and fullerenes generating efficiently the active oxygen forms, allows to improve considerably the efficiency of the photosensitizers' photodynamic action. Fullerenes in conjugates have an additional function as transporters. Fullerene lipophilicity facilitates the conjugate transfer across the membrane of the cancer cell.
The photoinduced activity in vitro on throat carcinoma cells of man Hep-2 was studied for the dyads 70a and 70b, synthesized on the base of tetraphenyl porphyrin and C60 derivative, potentially giving an efficient electron transfer (Figure 17).[73] The compound 70a was produced by the condensation of 5-(4-amydophenyl)-10,15,20-tris(4-metoxyphenyl)porphyrin and 1,2-dihydro-1,2-methane fullerene[60]-61-carboxylate.[74] The metal complex 70b was synthesized by the dyad 70a treatment with zinc acetate. The presence of methoxy groups in the porphyrin phenyl cycles as well as Zn in the porphyrin core increased its electron-donor characteristics. As a result of the tests it was stated that both dyads were capable to generate singlet oxygen, demonstrating a significant dependence of its
production on the solvent's polarity (0.80 for the compound 70a and 0.62 for the compound 70b in toluene and 0.18 and 0.04, respectively, in DMF). The dyads 70a and 70b were accumulated in the cells Hep-2 in less than 4 hours. The porphyrin-fullerene phototoxicity was decreasing
in the order P-C >ZnPC >P. Inactivation of 80 % cancer
60 60
cells was observed to take place for P-C60 after irradiation during 15 min. The high phototoxic effect was preserved even in the absence of oxygen, and the photoinduced decay of cancer cells for P-C60 in the argon medium was higher than for the free porphyrin under aerobic conditions. Depending on microenvironment when the dyads were localized in cancer cells, their photo decay was carried out either by the action of singlet oxygen or under a low oxygen concentration, due to the other active oxygen forms. Under anaerobic conditions the apoptosis process along the caspase-3-dependent pathway (58 % of apoptotic cells) was changed by the prevalence of necrotic phenomena. Thus, it was shown that the molecular systems synthesized, obtaining the photoinduced charge-separated state are promising models for the cancer cells inactivation by the PDT.
Rather high quantum yield of singlet oxygen was observed also for the dyads 71 and 72 (0.62-0.63) with an efficient electron transfer (Figure 18).[75] The dyads
O
O
48 R = Ethyl
49 R = Hexadecyl
O V^O^
Figure 12. Structures of pentads with additional alkyl substituents 48 and 49.
71 and 72 were synthesized by the interaction of the cor-
responding hydroxyiminomethyl substituted derivatives of chlorin p6 cycloimide with C60 in the presence of diace-toxyiodobenzene.[76]
The possibility of porphyrin-fullerene C60 dyad 74 application was studied (Scheme 17), containing 3 carbazoyl groups at the weso-positions of the tetrapyrrolic macrocycle, and its polycationic derivative 75 for the photodynamic inactivation of the cells Staphylococcus aureus}-17] The dyad
74 was produced applying the reaction of 1,3-dipolar linking by the interaction of 5-(4-formylphenyl)-10,15,20-tris[3-
(4-ethylcarbazole)]porphyrin 73, ^-methylglycine and C60. The exhausting dyad methylation with dimethylsulphate yielded the cationic derivative 75.
The spectroscopic properties of the dyads concerned were studied in homogeneous media of different polarity as well as in a biometric system toluene/sodiumbis(2-ethyl-hexyl)sulfosuccinate (AOT)/water, forming the reversed micelles. Singlet oxygen production for the compounds obtained depended significantly on the polarity of the solvent. A considerable quantum yield of singlet oxygen generation for the dyad 74 was observed in toluene (0.56), however in a more polar solvent, dimethylformamide, it decreased
significantly (0.01) owing to the stabilization of the charge-separated state. Rather high quantum yield of the singlet oxygen generation was observed for both dyads (0.50 for 74 and 0.46 for 75) in the biomimetic system.
The photoinactivating power of the dyads 74 and 75 was examined using the Staphylococcus aureus cells suspension. When using 5 ^m of the dyad 75 and the exposure to light in the range (350-800 nm) during 30 min complete cells inactivation was observed. Under the same conditions lower photo cytotoxic effect was observed for the dyad 74. The photoinactivation of Staphylococcus aureus using the dyad 75 was stated by the authors to be less efficient than when using the cationic derivatives of the parent compounds
DAC60+ and TCP4+.
60
A highly water-soluble dyad 78 (Scheme 18) based on chlorin e6 amine derivative 76 and polyanionic derivative C60 77, possessing high solubility in water, was produced by the authors,[34] and its spectral properties and photochemical activity were studied. Strong quenching of the chlorin fluorescence as well as the dependence of the fluorescence quenching extent on the solvent's polarity indicated an efficient electron transfer from macrocycle to fullerene. The dyad synthesized was stated to possess a pronounced
OR OR
O
O "OR
O
O
R =
R = tert-butyl (a), H (b)
51a,b
Figure 13. Structures of pentads with dendrons moieties 50 and 51.
photochemical activity more than 10 times that of the free chlorin, which indicates the prospects of water-soluble chlorin-fullerene production as promising photosensitizers for medicine.
Fullerene is known to transform the light energy into vibrational energy causing the temperature increase. In this connection, multimeric conjugate of chlorin e6, folate and C60 79 presents a special interest for application in the combined photothermal/photodynamic therapy of cancer.[78] The conjugate 79 synthesis is shown at the Scheme 19. Chlorin e6 and folate were activated with DCC and ^-hydroxysuccin-imide (NHS) to form the respective succinates. Polyethylene glycol (PEG) was treated with succinic anhydride in the presence of DMAP and TEA and the di-carboxylated PEG deriva-
tive obtained successively interacted with DCC and NHS, and the ethylenediamine excess forming NH2-PEG-NH2. C60 reacted with NH2-PEG-NH2, activated with chlorin e6-NHS and folate-NHS to give multidimensional conjugate 79.
The anticancer activity of multidimensional conjugate was studied both in vitro and on the cells of KB human carcinoma with high expression of the folate receptors. The temperature on the tumor's surface of mice with the KB tumor was shown to amount to 44 °C after the conjugate administration. Hyperthermal conditions and high quantum yield of the singlet oxygen generation by multimeric conjugate resulted in a significant regression of the tumor's volume in vivo. The conjugate 79 also inhibited efficiently the arthritis development of mice.
Figure 14. Structures of tetrad 52, pentad 53 and molecular system 54. Макрогетер0циmbl /Macroheterocycles 2018 11 (4) 339-362
CHO
Br
57
N I
Me
\ = R1N3
-N. .N==<
p' N
OR
A-A /T V /=*
Zn T-C
or2
R2 = RrN «.N N
Scheme 15. Synthesis of pentad 59. Reagents and conditions: i - Br(CH2)3Br, K2CO3, DMF; ii - 4-hydroxybenzaldehyde, K2CO3, DMF; iii - V-methylglycine, C60, toluene, reflux; iv - R1N3, sodium ascorbate, CuSO4-5H2O, CHCl3/EtOH/H2O (12:1:1).
O
O
O
O
The conjugate of chlorin e6 with fullerene C70 modified with three residues of malonic acid may serve as an example of the efficient phototheranostic nanoplatform for the PDT application with an improved accumulation in tumor cells.[79] The possibility of production of nanovesi-cles based on amphiphilic fullerene derivatives for diag-
nostics and therapy of cancer in vivo was demonstrated by the authors for the first time. The amphiphilic conjugate was synthesized by the condensation of chlorin e6 preliminary modified with 1,10-diamino-4,7-dioxadecane (OEG2) with fullerene C70 derivative containing three residues of the malonic acid (Scheme 20). The conjugate obtained 80
Scheme 16. Synthetic pathways for obtaining of polyad 65a and the metal complex 65b. Reagents and conditions: i - BF3OEt2, CHCl3 (a), />-chloranil (b), KOH, THF/EtOH, reflux (c); ii - 4-ferrocenylaniline, SOCl2, pyridine, toluene, reflux (a), formyl-protected aniline (b), H2SO TFA, CHCl3 (c); iii - V-methylglycine, C60, toluene, reflux (a), Zn(OAc)2/MeOH (b).
67
MeO.
O
68
MeO.
Figure 16. Structures of amphiphilic dyads 67-69.
70a,b
M = 2H (a), Zn (b)
MeO2C
OMe
71
Me _
( H „ _ ,
O N
O=C (CH2)3OH
' N-
O
Figure 17. Structure of dyads obtained from the tetraphenylporphyrin derivative and C60.
Figure 18. Structures of chlorin p6 cycloimide - C60 dyads 71 and 72. 6 60
R2
Vnh n«/ R^ /—R2
T-N HN"\
R2
TCP4+
Scheme 17. Synthesis of porphyrin-fullerene dyad 74 containing carbazoyl grous and its polycationic derivative 75.
H2N
h o o
o
V^n' oH
H2N
H2N-PEGNH
H2N-PEGNH
HN—PEG
o
NH \
NH .PEG
NH
HN,
NH
fH&NH-^
H2N-PE^NH'^HN-PEG-NH2
Folate
p*
Folate,^ 0=C,
c=o I
HN-PE^NH
0=C I
HN,
hn-pegnh*
HN—PEG
V
NH PEG
NH \ NH
0
Ce6
HN_
hn-pegnh
NH
, ^ 1 P* >=UYnh-0^ c=o
MJ I
HN—PEG''
NH
79
Scheme 19. Synthesis of multimeric conjugate 79. Reagents: i - C benzene; ii - Ce6-NHS, folate-NHS.
OEG2
BocHN ____NH2
BocHN ^____q^v.- NHCe6
m
H2N^O^NHCe6 Ce6-OEG2
Ces = chlorin eg
NHCe6
80
Scheme 20. Synthesis of chlorin e6 and C70 amphiphilic conjugate 80. Reagents and conditions: i - Boc2O, DCM; ii - EDC/NHS, Ce6, DMSO; iii - TFA, Na2CO3; iv - BrCH(COOC2H5)2, DBU; v - NaH; vi -EDC/NHS, Ce6-OEG2, DMSO.
O
O
O
O
formed vesicles with a high chlorin e6 contents (up to 57 %), demonstrated extensive absorption in the long-wave region and accumulated well in the cancer cells of human lung adenocarcinoma A549, exhibiting strong activity in vivo, was biocompatible and well eliminated from the organism.
Conclusions
Thus, the achievements in the field of porphyrin-and chlorin-fullerene synthesis made these compounds available and gave the opportunity to produce a wide range of artificial photosynthetic models beginning with simple dyads and triads till multichromophoric systems in order to study the relations between the structure and photo -chemical activity and to approach to their application when preparing the models to study the mechanism of natural photosynthesis, artificial conversion of solar energy, pho-toelectrical devices. It was shown that the rate and the efficiency of the energy and electron transfer are significantly influenced by the alteration of the distance and orientation of the donor- and acceptor-moieties, the nature of solvent and the linker between the photoactive moieties. The quantum yields and the charge-separation lifetime are the parameters, characterizing the progress in artificial photosynthetic systems. The application of the multistep electron transfer concept, which is realized in the natural photosynthesis, along well-defined redox gradients, is one of the effective approaches, which allows to prolong the lifetime of the charge-separated state. The compounds were produced as a result of the design and synthesis of a number of covalently linked porphyrin-fullerene systems, which have a fast charge separation with extremely slow charge recombination and the lifetime of the charge-separated state is comparable and even exceeded the lifetime of the charge-separated state in the natural bacterial photosynthetic reaction center.
The use of porphyrin- and chlorin-fullerene structures in medicine are extremely promising. The conjunction of porphyrins and chlorins, absorbing intensively in the visible region of spectrum, and fullerenes, generating various active forms of oxygen efficiently, allows to increase the efficiency of the photodynamic effect of the photosensitizer. The examples published witness the prospects of the application of such compounds in antimicrobial photodynamic inactivation, the combined photothermal/photodynamic therapy of cancer and in phototheranostics.
Acknowledgements. The work was supported by the Ministry of Education and Science of the Russian Federation, government task no 4.9596.2017/8.9.
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Received 04.06.2018 Accepted 27.07.2018
