Synthesis of N-phytochlorin-substituted[60]fulleropyrrolidines

ALEXANDER EFIMOV1*, NIKOLAI V. TKATCHENKO1, PIRJO VAINIOTALO2 AND HELGE LEMMETYINEN1

1Institute of Materials Chemistry, Tampere University of Technology, PO Box 541, FIN-33101 Tampere, Finland2Department of Chemistry, University of Joensuu, PO Box 111, FIN-80101 Joensuu, Finland

Received 11 June 2001Accepted 6 August 2001

ABSTRACT: A series of new phytochlorin–fullerene dyads was prepared. Synthetic pathway includes attachment ofglycine to aldehyde-containing phytochlorins via reductive amination, where 3- and 7-carbonyl-substitutedpheophorbides exhibit surprisingly different reactivity. The appropriate conditions of reactions (e.g. solvents andreducing agents) were determined in each case. Copyright � 2001 John Wiley & Sons, Ltd.

KEYWORDS: pheophorbide; phytochlorin; fullerene; photoinduced electron transfer; donor–acceptor dyad

INTRODUCTION

Many recent publications concern the synthesis of donor–acceptor dyads containing fullerene and porphyrin orchlorin moieties [1–5]. One of the most common methodsof coupling of these donors and acceptors involves areaction of fullerene with N-methylglycine and formylcontaining macrocycle. Addition of a reactive azamethineylide across the juncture of two 6-rings in the fullereneresults in a 2-substituted N-methyl-pyrrolidinofullerene [6–8]. At the same time, synthesis of chlorins attached to thenitrogen atom of pyrrolidinofullerenes is not developed. Inthis paper we present an example of synthesis of suchmolecules, where the longer bridge between donor andacceptor could increase the charge-separated state lifetimerelative to 2-chlorin-substituted pyrrolidinofullerene [7].

EXPERIMENTAL

The solvents used in the synthesis and separations were ofanalytical grade, and were distilled prior to use. Buck-minsterfullerene C60 (�98%) was purchased from Fluka(Buchs, Switzerland).

The 1H NMR spectra were run on a 300 MHz VarianMercury spectrometer. Electrospray ionization (ESI) massspectra were measured using a Fourier transform ioncyclotron resonance mass spectrometer (Bruker BioA-pex47e). The compounds were first dissolved in chloroformor dichloromethane at a concentration of 1 mg ml�1 and10 ml of these solutions were diluted to 1 ml with 60:40:0.1toluene:methanol:trifluoroacetic acid solution.

3-(2-Phenyl-[60]fulleropyrrolidin-1-ylmethyl)-3-deethylphytochlorin Methyl Ester (9)

To a stirred solution of 60 mg of glycine tert-butyl esterhydrochloride (0.36 mmol) and 60 mg of pyropheophorbided (PPd) methyl ester (0.11 mmol) in 500 ml of ethanol, a260 mg of sodium cyanoborohydride (4.1 mmol) was addedand the reaction mixture was stirred under argon atmospherefor 72 h. Then the solvent was removed under reducedpressure and the dry residue was dissolved in 100 ml ofchloroform. The organic phase was washed with 5 � 200 mlof water, dried on anhydrous sodium sulfate and evaporated.The solid residue was dissolved in 5 ml of trifluoroaceticacid and stirred for 1 h. The reaction mixture wasevaporated to dryness and the residue was recrystallizedfrom chloroform/carbon tetrachloride (2/20 ml). The pre-cipitate was collected by filtration and dried in air, giving28 mg of glycine-substituted chlorin 8 (yield 41%). 28 mgof 8 (0.046 mmol), 35 mg of C60 (0.048 mmol) and 42 mgof benzaldehyde (0.21 mmol) were refluxed under argonatmosphere in 300 ml of dry toluene. After 4 h the reactionmixture was cooled to room temperature and passed througha silica gel layer (Silica 100; height of layer 20 mm, internaldiameter (ID) of column 40 mm). The unreacted fullereneand benzaldehyde were eluted with 150 ml of toluene. Thedyad was eluted from sorbent with 100 ml of chloroform.The solution was evaporated and the residue was recrys-tallized from chloroform/ethanol (2/100 ml). The precipi-tate mainly containing the dyad was collected by filtrationand final purification was performed on high-performancethin-layer chromatography (HPTLC) plates 20 � 10 cm(Merck), using methylene chloride/ethanol 50/1 as eluent.Yield of pure compound 9 was 9.3 mg (6.1% based onstarting PPd). ESI MS m/z 1374.10 (M�), C101H43O3N5

requires 1374.2. 1H NMR (300 MHz, CDCl3) �H: 10.2 (s,5-H), 9.58 (s, 10-H), 8.65 (s, 20-H), 7.79–7.59 (br m,Ar-H), 7.58–7.47 (br m, Ar-H), 5.7 (AX spin system, d,�2J� = 13.54 Hz, 5�-CH2), 5.56 (s, 2�-H), 5.29, 5.13 (AB spinsystem, �2J� = 20 Hz, 132-CH2), 4.88 (AX spin system, d,�2J� = 13.54 Hz, 5�-CH2), 4.79 (AX spin system, d, �2J�

Journal of Porphyrins and PhthalocyaninesJ. Porphyrins Phthalocyanines 2001; 5: 835–838

DOI: 10.1002/jpp.550

Copyright � 2001 John Wiley & Sons, Ltd.

*Correspondence to: A. Efimov, Institute of Materials Chemistry,Tampere University of Technology, PO Box 541, FIN-33101,Tampere, Finland.Email: efimov@kempc17.me.tut.fi

= 10.87 Hz, 31-CH2), 4.53 (AX spin system, d, �2J� =10.87 Hz, 31-CH2), 4.51 (m, 18-CH), 4.33 (br, 17-CH),3.76 (overlapping quartet (oq), 81-CH2), 3.70 (s, 121-CH3),3.66 (m, 21-CH3), 3.61 (m, 71-CH3), 3.52 (s, 173-OCH3),2.78–2.47, 2.39–2.15 (m, 171-, 172-CH2), 1.88–1.79 (m,181-CH3), 1.73 (t, �3J� = 7.32 Hz, 82-CH3). UV-vis (CHCl3),�max (log�) 257 (5.016), 320 (4.6581), 413 (4.9778), 507(3.9554), 539 (3.9222), 607 (3.8968), 664 (4.6535).

3-Vinyl-3-deethyl-7-(2-phenyl-[60]fulleropyrrolidin-1-ylmethyl)-7-desmethyl-131-desoxy-131-hydroxyphytochlorin Methyl Ester (10)

30 mg of pyropheophorbide b (PPb) methyl ester(0.05 mmol) was dissolved in 120 ml of ethanol and0.47 ml of a 0.16 M solution of potassium glycinate(0.075 mmol) in water was added. The reaction mixturewas stirred for 12 h at 60°C under argon. Then 0.1 ml of a0.9 M solution of potassium glycinate (0.09 mmol) in waterwas added and the reaction mixture was stirred at 50°C for4 h. The reaction mixture was cooled to room temperatureand 120 mg of sodium borohydride (3.17 mmol) was added.After 1 h of stirring the solvent was partially evaporated for50 ml of volume and the solution was poured into 50 ml ofwater. Then 2 N HCl was added dropwise to the reactionmixture until pH 5 was reached. At this point theprecipitation of glycine-substituted chlorin 3 took place.The precipitate was collected by filtration and dried in air;yield 12 mg (36%). 12 mg of 3 (0.019 mmol), 15 mg of C60

(0.02 mmol) and 21 mg of benzaldehyde (0.2 mmol) wererefluxed under argon atmosphere in 50 ml of dry toluene.After 4 h the solvent was removed under reduced pressureand the dry residue was redissolved in 50 ml of chloroform.The precipitate of unreacted fullerene was removed byfiltration and the reaction mixture was chromatographed ona silica gel column (Silica 60; height of layer 200 mm, ID ofcolumn 20 mm, elution with chloroform/acetone: 50/1, v/v)to give dyad 10. After additional chromatographic purifica-tion (Silica 60; height of layer 200 mm, ID of column20 mm, elution with chloroform/acetone: 80/1, v/v) 2.2 mgof pure dyad 10 was obtained (yield 3.1% based on startingPPb). ESI MS m/z 1388.39 (M�), C102H45O3N5 requires1388.4. 1H NMR (300 MHz, CDCl3) �H: 11.01 (s, 5-H), 9.79(s, 10-H), 8.93 (s, 20-H), 8.62–8.54 (m, 31-CH), 7.78–7.59(br m, Ar-H), 7.56–7.49 (br m, Ar-H), 6.57 (br, 131-OH),6.55–6.32 (m, 32-CH2), 5.77 (AX spin system, d, �2J� =13.46 Hz, 5�-CH2), 5.54 (s, 2�-H), 5.43–5.27 (m, 131-H),4.93–4.38 (m, 5�-CH2, 132-CH2, 71-CH2, 18-CH), 4.16(br, 17-CH), 3.68 (s, 121-CH3), 3.66–3.54 (m, 81-CH2, 21-CH3), 3.47 (m, 173-OCH3), 2.85–2.25 (m, 171-, 172-CH2),2.04–1.93 (m, 181-CH3), 1.89–1.78 (m, 82-CH3). UV-vis(CHCl3), �max (log�) 257 (4.9571), 411 (5.1139), 507(4.058), 594 (3.5763), 648 (4.3995).

RESULTS AND DISCUSSION

The synthetic pathway includes preparation of the glycine-derivative of phytochlorin and its coupling with fullerene inrefluxing toluene. The key intermediate of the synthesis ischlorin, substituted with N-methylenoglycine fragment. Itcan be obtained in many ways; one of these is reductiveamination of the formyl derivative of phytochlorin. In ourwork pyropheophorbide d (PPd) 1 and pyropheophorbide b(PPb) 2 were used (Fig. 1) [9, 10]. Usually reductive

amination is carried out under mild conditions and giveshigh yield with an enormous set of aldehydes. Traditionallyit is performed as a two-step or two-step, one-pot reaction inmethanol, methanol–water, ethanol or dichloroethane withNaBH4 [11], NaBH3CN [12] or NaBH(OAc)3 [13] asreducing agent. However, the solubility of glycine andchlorins, as well sterical hindrance of the latter, restricts thechoice of solvents.

Surprisingly, the aldehyde moieties of PPb and PPd showdifferent reactivity. The reaction speed of the PPb formylgroup with different glycine derivatives (potassium glyci-nate (GlyOK), glycine tert-butyl ester (GlyOtBu) glycinetert-butyl ester hydrochloride (GlyOtBu�HCl)) is lower thanfor PPd. At the same time the carbonyl oxygen of the PPbcyclopentanone ring can be reduced to alcohol withoutreduction of the aldehyde group.

The glycine derivative of PPb 3 was obtained by a two-step process. First, a 10 molar excess of GlyOK is reactedwith PPb in ethanol at 60°C. The subsequent reduction ofthe Shiff’s base was performed at room temperature usingsodium borohydride. It should be noted that the reaction ofPPb at room temperature with a 10 molar excess of GlyOKin tetrahydrofuran (THF) and following reduction byNaBH4 results in 3-Gly-substituted phytochlorin containingfree acid residue at the 173 position, which cannot be used inreaction with fullerene due to its insolubility in toluene. Onthe other hand, the formyl group remains intact in mostoperation conditions. Thus, reaction of PPb with GlyOtBuin ethanol at room temperature followed by NaBH4

treatment produces compounds 4 and 5 (Fig. 1), containingeither a reduced cyclopentanone ring or the reducedcyclopentanone ring and a formyl group, respectively.Formation of the Shiff’s base was not observed in thereaction with GlyOtBu nor GlyOtBu�HCl in ethanol, THF,dichloroethane, or methylene chloride.

In the case of PPd, the combination of ethanol as solvent,GlyOtBu�HCl as amine component, and sodium cyanoboro-hydride as reducing agent was only found to be suitable forsynthesis of the aminoacid-derivative 6 with appropriateyield (Fig. 2). The dominating side process is transesteri-fication of the tert-butyl ester of the glycine moiety. Theamount of transesterified product 7 was decreased byperforming the reaction at room temperature, but therequired reaction time was 4 days. The chromatographic

Fig. 1. Compounds 1–5.

Copyright � 2001 John Wiley & Sons, Ltd. J. Porphyrins Phthalocyanines 2001; 5: 835–838

836 A. EFIMOV ET AL.

separation of ethyl and tert-butyl esters seemed to bedifficult due to the very close Rf values of these compounds.Therefore, the mixture of chlorins was treated withtrifluoroacetic acid and target compound 8 was separatedby crystallization with 20% yield (on the basis of startingPPd).

When the reaction of PPd with GlyOtBu�HCl was carriedout in refluxing ethanol the full conversion of phytochlorininto the Shiff’s base was achieved in 3 h, but completetransesterification of tert-butyl ester took place at the sametime. Reduction of the Shiff’s base with sodium borohydridealso promotes the transesterification of tert-butyl ester andthe final yield of the desirable glycine-derivative of PPd 8does not exceed 10%.

The formation of the Shiff’s base of PPd with GlyOtBu

and GlyOtBu�HCl was found to be very selective to solvent.Thus, no reaction was observed in benzene, acetonitrile,dioxane, THF, methylene chloride, dichloroethane, tolueneand tert-butanol at room temperature nor at their boilingpoints.

Reaction of PPd with GlyOK in ethanol at 40°C producesa glycine-derivative of PPd with low yield, and increasing ofthe temperature up to 50°C results in complete hydrolysis ofthe methyl ester of the propionic tail of phytochlorin. It isinteresting to note that the cyclopentanone ring of PPdremains intact in this case, despite the large excess ofsodium borohydride (the dyad 9, synthesized from thiscompound contains a non-reduced cyclopentanone ring; theintermediate aminoacid was used in synthesis without NMRcharacterization). Formation of a Shiff’s base with GlyOKwas not observed in THF at room temperature as well as at40°C.

The coupling of chlorin-aminoacid with fullerene wascarried out in toluene according to a well-known procedureusing the benzaldehyde as carbonyl component. Practicallyno difference was observed in the reactivity of intermediates3 and 8. In both cases the reaction time of 4 h was enoughfor complete conversion of the starting chlorin. The twomolar excess of fullerene and large (up to 10 molar) excessof benzaldehyde were required for improving the yield ofthe dyad.

The purification of dyads 9 and 10 was a complicated taskdue to a large amount of side products with similar Rf.Finally, the best separation was obtained using a combina-tion of flash chromatography in toluene in order to removeunreacted fullerene and benzaldehyde and subsequentcombination of HPTLC and crystallization. Despite bothdyads containing chiral carbon, no separation of stereo-isomers was observed. The yields of compounds 9 and 10were 6% and 3% based on starting PPb and PPd,respectively.

Comparison of the absorption maxima of dyads (Table 1)shows influence of the linker structure on the spectralproperties of the chromophore. Detailed photochemicalstudies of synthesized phytochlorin–fullerene dyads such asfluorescence lifetime measurements and time-resolvedtransient absorption spectroscopy, as well as the behaviorof these compounds in Langmuir–Blodgett films, areunderway.

CONCLUSION

In conclusion, we have developed a new approach forconstructing fullerene–phytochlorin dyads. The novelglycine-derivatives of phytochlorins used in this study havelarge potential as building blocks for not only synthesis of

Fig. 2. Compounds 6–12.

Table 1. Comparison of absorption maxima of different dyads

Compound Absorption maxima in toluene (nm) Ref.

9 412 506 536 609 665

10 412 505 – 596 650

11 417 511 541 616 673 [14]

12 429 516 547 611 668 [14]

Copyright � 2001 John Wiley & Sons, Ltd. J. Porphyrins Phthalocyanines 2001; 5: 835–838

SYNTHESIS OF N-PHYTOCHLORIN-SUBSTITUTED [60]FULLEROPYRROLIDINS 837

the donor–acceptor systems, but also for constructing avariety of biologically significant molecules.

Acknowledgement

Financial support from the Academy of Finland is gratefullyacknowledged.

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