A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.

, 1990 (1994).2,9,16,23-Tetra-p-n-butylbenzyloxy-, 2,9,16,23-tetradiphenylrnethoxy-, 2,9,16,23-tetramethoxymethoxy-, and 1,8,15,22-tetra-p-n-butylbenzyloxyphthalocyanines were synthesized from the appropriate phthalonitriles. Metal-free phthalocyanines were converted to their zinc derivatives. Cleavage from the appropriate precursor with trifluoroacetic acid produced 2,9,16,23-tetrahydroxyphthalocyanine and 1,8,15,22-tetrahydroxyphthalocyanine and their zinc derivatives. NMR spectroscopy revealed that all the 2,9,16,23-tetrasubstituted phthalocyanines are the usual mixtures of the 2,9,16,23, 2,9,16,24, 2,9,17,24, and 2,10,16,24 isomers, but the two 1,8,15,22-tetrasubstituted phthalocyanines were formed as pure single isomers.CLIFFORD C. LEZNOFF, MOUGANG Hu, COLIN R. MCARTHUR, YONGNIAN Qn' l et JOHAN E. VAN LIER Can. J. Chem. 72, 1990.Utilisant les phtalonitriles approprits comme produits de dCpart, on a synthCtisC les 2,9,16,23-tCtra-p-n-butylbenzyloxy-, 2,9,16,23-tttraphtnylmCthoxy-, 2,9,16,23-tCtramtthoxym6thoxy-et 1,8,15,22-tttra-p-n-butylbenzyloxyphtalocyanines. On a transform6 les phtalocyanines libres de mttal en dCrivts zinciques. Le clivage du prtcurseur approprik avec de l'acide trifluoroacttique conduit h la 2,9,16,23-tttrahydroxyphtalocyanine et h la 1,8,15,22-tCtrahydroxyphtalocyanine et h leurs dCrivts zinciques. La RMN rtvttle que toutes les phtalocyanines tCtrasubstitu6es en 2,9,16,23 sont formCes des mClanges habituels des isombres 2,9,16,23, 2,9,16,24, 2,9,17,24 et 2,10,16,24; toutefois, les deux phtalocyanines substitu6es en 1,8,15,22 sont des isomkres purs.

Condensation of 4-substituted phthalonitriles with lithium 2-N,N-dimethylaminoethoxide in 2-N,N-dimethylaminoethanol gives a non-statistical mixture of tetrasubstituted phthalocyanines at room temperature or lower while 3-substituted phthalonitriles similarly condense with lithium octan-l-olate in octan-1-ol giving 1,8,15,22-tetrasubstituted phthalocyanines as pure isomers.Classically, phthalocyanines (Pcs) have been prepared by high temperature (200-300'C) fusion methods from phthalic anhydride or its derivativesr or by condensation of phthalonitriles with lithium pentan-l-olate in refluxing pentan-1-ol (135 "C;.2.: 1,3-Diiminoisoindolines, prepared from phthalonitriles, are readily condensed to phthalocyanines in refluxing 2-N,Ndimethylaminoethanol (DMAE) (135 "C).4.5 Lower temperature synthesis of phthalocyanines in refluxing butan-l-ol (80 "C) using DBU6.7 as a base is also common. In condensations in our laboratory using diminoisoindolines in DMAE, we had noticed that phthalocyanine formation begins to occur at a temperature as low as 90 oC even though the standard procedure is accomplished at 135 "C. We thought of preparing the alkoxide of this solvent with lithium metal and using this alkoxide in phthalocyanine formation, a seeming trivial modification of existing protocol but one that has important ramifications. We subsequently showed that lithium octan-I -olate in octan-l -ol was also successful for phthalocyanine formation at room temperature but that lithium pentanl-olate in pentan'l-ol or lower molecular weight alkoxides in lower alcohols did not give phthalocyanines at lower temperatures in accordance with the literature.l'2 Thus, condensation of phthalonitrile 1, 4-neopentoxyphthalonitriler3 2 or 4-nitrophthaloninile 3 in lithium DMAE at 50, 20 or 3 "C and 3-neopentoxyphthalonitrilera 4, 3-p-butylbenzyloxyphthalonitriler2 5 or 3-methoxyphthalonitriler5 6 in lithium octan-I -olate in octan-I -ol at 20 "C readily took place. Normal work-up of the reactions from l-3 gave phthalocyanine 7, 2,9,16,23-tetraneopentoxyphthalocyaniner3 8 and 2,9, | 6,23 -tetr anitrophthalocyanines' I 6 9, while treatment of the reactions from 44 with zinc acetate gave 1,8,15,22-tetraneopentoxyphthalocyaninato zinc(u) 3,9 R = 4-NOz; 4,10 R = 3-OCHzCMeg; 5'11 F = 3-OCH2Ph-PBU; 6,12 R = 3-OMe;7-9M=He;10-12M=Zn Scheme I

2,3,9, I 0-Tetrakis(3,3-dimethyl-I -butynyl)phthalocyanine and 2,3,9,10-tetramethoxyphthalocyanine were prepared by the condensation of a "half' phthalocyanine intermediate (prepared from 4,5-bis(3,3-dimethyl-l-butynyl)phthalonitrile or phthalonitrile) with phthalonitrile and 4,5-dimethoxyphthalonitrile respectively.Recently, much interest has been focussed on "opposite" and "adjacent" substituted phthalocyanines (Pcs) Analysis of the crude products, derived from 1-3 by FAB mass (ms) and lll nuclear magnetic resonance (NMR) spectroscopy indicated that the predominant products from I and 2 were the "half' phthatocyanine intermediates (dimers) 4 and 5,6 while 3 gave only a trace of dimer 6. In the reacdon of I and 2, minor amounts of the "quarter" phthalocyanine intermediate (monomer) 7 and 8 were detected, but the reaction of 3 gave moslly monomer 9.Attempts were made at purifying 4 by column chromatography, but demetallation ol the lithium and hydrolysis of the methoxy group likely occurred. Gel-permeation chromatography (GPC) using SX-4 Beads (Bio-Rad) and terrahydrofuran (THF) as the eluting solvent was attempted but partial demetallation occurred. It was decided that the crude intermediates 4 and 5 would be used in the svnthesis of an adjacent Pc.Crude 4 was reated with a large excess of 2 in 2-N,Ndimethylaminoethanol (DMAE) at 75o C. After 3 h, Zn(OAc)2 was added and the temperature lowered to 600 C and allowed to stir for an additional 24 h. The reaction mixture was then diluted with 207c methanol/water and the pigment dried and collected. The crude product was lhen suspended in benzene until all soluble Pcs were completely removed. Flash chromatography using chloroform as the eluting solvent, was performed on the soluble Pcs collected from the above extraction. The first of five coloured fractions contained a trace amount of a zinc octaalkynylphthalocyanine (10), t}te second fraction contained a mixture of zinc octaalkynyl-(10), hexaalkynyl-(11), and tetraalkynylphthalocyanines (12) plus possibly (13), rhe third band was pure 2,3,9,lGtetrakis(3,3-dimethyl-1-butynyl)phthalocyaninato zinc GD7 (f2), the fourth band was a mixture of (12) and 2,3-bis(3,3-dimethyl-l-b-utynyl)phthalocyaninato zinc (II) (14), and rhe fifth band was ptrre 14'. All fractions containing 12 and,74 were further purified by GPC on SX-Z beads (Bio-Rad) with THF as the eluring solvenl All Pcs were separated after one column and the yields of 12 and 14 were 20Vo and l07o respectively, while only trace amounts of 10 and 12 were obtained (less than l7o) (Scheme). The lH NMR specrrum of 12 in pyridine-dj (10-3 M at 300 K) exhibits. in the aromatic region, two singlets of equal intensity along with two multiplets for the protons of the unsubstituted benzo rings. The combined intensities of the two singlets is equal to the intensity of each multiplet as it should be for 12. As the concentration was increased to 10-2 M, the two singlets converged, most likely rJue to aggregation.Similarly, treatment of the unsubstituted dimer 2 with ...

. Can. J. Chem. 71, 742 (1993).The spectral and electrochemical properties of tetrabenzo [5, lO,lS]triazaporphine (TBTAP) and its magnesium derivatives having a long alkyl chain attached to the meso carbon have been studied. Both metal-free and metallated species show typical metal-free phthalocyanine-like spectra. Two reduction and two oxidation redox couples have been observed. The cation, anion, and dianion species of these porphyrin derivatives have been electrochemically generated and their electronic spectra are recorded.