The synthesis and characterisation of carbohydrate-functionalised porphyrazines

Article abstract of DOI:10.1016/j.dyepig.2010.05.002

A synthetic pathway to the incorporation of mono- and disaccharide carbohydrate moieties into porphyrazine systems was demonstrated. A range of selectively protected monosaccharide precursors was coupled to a small variety of phthalonitriles; the intermediates were co-macrocyclised to form hybrid porphyrazines in Linstead macrocyclisation reactions. Demetallisation of Mg-porphyrazine products was readily effected to afford the free-base pigments, which were subsequently converted into their zinc or nickel complexes. Some porphyrazines were deprotected of their isopropylidene groups (on the carbohydrate moieties) under acidic conditions to reveal polar OH groups. The extraction coefficients of the porphyrazines between 2-octanol and phosphate buffered saline solution were measured. Comparison of the partition coefficients of the carbohydrate-substituted porphyrazines and their deprotected counterparts revealed that structural alteration offers a way to significantly increase the hydrophilicity of substituted porphyrazines.

Full text of DOI:10.1016/j.dyepig.2010.05.002

Dyes and Pigments 88 (2011) 65e74
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
The synthesis and characterisation of carbohydrate-functionalised porphyrazines
*
D. Bradley G. Williams , G. Bheki Mbatha
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park 2006, Johannesburg, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic pathway to the incorporation of mono- and disaccharide carbohydrate moieties into por-
phyrazine systems was demonstrated. A range of selectively protected monosaccharide precursors was
coupled to a small variety of phthalonitriles; the intermediates were co-macrocyclised to form hybrid
porphyrazines in Linstead macrocyclisation reactions. Demetallisation of Mg-porphyrazine products was
readily effected to afford the free-base pigments, which were subsequently converted into their zinc or
nickel complexes. Some porphyrazines were deprotected of their isopropylidene groups (on the carbo-
hydrate moieties) under acidic conditions to reveal polar OH groups. The extraction coefficients of the
porphyrazines between 2-octanol and phosphate buffered saline solution were measured. Comparison of
the partition coefficients of the carbohydrate-substituted porphyrazines and their deprotected coun-
terparts revealed that structural alteration offers a way to significantly increase the hydrophilicity of
substituted porphyrazines.
Received 25 March 2010
Received in revised form
7 May 2010
Accepted 10 May 2010
Available online 19 May 2010
Keywords:
Porphyrazine
Carbohydrate
Macrocycle
Photodynamic therapy
Extraction coefficient
Chiral
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
more general interest than exclusively in the medical application of
these macrocycles. In this paper, we report the synthesis of por-
The synthesis, properties and application of porphyrazines have
received increasing attention in recent years [1e3], especially their
potential role as photosensitisers in photodynamic therapy [4e8]. A
continuing problem in photodynamic therapy is selectivity of
uptake of the photosensitiser by cancerous tissue, for which
a potential solution, is functionalisation of the photosensitiser with
a biological moiety (e.g. a carbohydrate) to assist its selective
uptake and improve its solubility. Substituted amphiphilic and
hydrophilic porphyrazines bearing both hydrophilic and hydro-
phobic moieties have been shown to be potent photosensitisers in
photodynamic therapy [9e12]. Such pigments should be suffi-
ciently hydrophilic to be administered as aqueous solutions so as to
ensure that they quickly reach the target tumour tissues once
administered and are rapidly eliminated from the body post clinic.
Carbohydrates play a central role in various biological recogni-
tion processes with many carbohydrate-derived therapeutics
undergoing clinical trials [13e16]. The idea of employing saccha-
rides as conjugates to manipulate drug distribution is also of
interest and has been used to good effect in other instances [17,18].
Additionally, deprotection of carbohydrate-substituted compounds
brings another advantage by increasing the solubility of the
molecules in aqueous media, a phenomenon which would be of
phyrazines with carbohydrate substituents, on metal complexation
(in the cavity) thereof and the removal of the isopropylidene pro-
tecting groups seated on the carbohydrate residues. We also report
on the influence on the hydrophilicity of the porphyrazine ring
system with structural alteration of the carbohydrate moieties as
measured against pigments 1 and 2 (Fig. 1).
2. Experimental
Under this section, only representative examples are given. Full
details for the preparation and analyses of all new compounds are
given under Supplementary Information (for compounds 6, 7,
10e12, 18, 21, 23, 25, 26, 28, 29, 35, 37e39, 41e43, 45e48, 50e66,
63e65). Copies of selected UVevis spectra are also reproduced.
All solvents used were purified according to the purification of
laboratory chemicals and the reactions were done under nitrogen
atmosphere [19]. Flash column chromatography was carried out on
Merck Kieselgel 60 (230e400 mesh) under nitrogen pressure. Thin-
layer chromatography was performed using Merck 60 F254 silica gel
sheets. NMR spectra were recorded on a Varian Gemini 300 MHz
spectrometer in CDCl3 or DMSO unless otherwise indicated. Elec-
tronic spectra were measured on a UVevisible160 An SHIMADZU
spectrophotometer, using a matched pair of 1 cm path length
quartz cuvettes. Melting points were determined on a REICHERT
Koffler hot stage melting point apparatus and are uncorrected. The
phosphate buffered saline solution was prepared by dissolving the
* Corresponding author. Tel.: þ27 115593431; fax: þ27 11 559 2819.
E-mail address: bwilliams@uj.ac.za (D.B.G. Williams).
0143-7208/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.dyepig.2010.05.002

66
D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
(2H, m), 3.40 (3H, s), 1.56 (3H, s), 1.39 (3H, s); 13C NMR (75 MHz,
CDCl3) dC: 157.3, 134.8, 129.1, 116.7, 115.5, 114.7, 114.4, 112.8, 109.7,
108.7, 84.9, 83.6, 81.7, 70.2, 55.4, 26.4, 25.0; FAB-MS: 367 ([M þ 1]þ),
333 ([MeOCH3e2H]þ), 307 ([MeOCH3eC2H4]þ); IR ymax (CHCl3)/
cmꢀ1: 3082, 2998, 2230, 1317, 1225, 1053, 703.
O
O
N
N
N
N
N
H
N
N
N
N
Mg N
N
H
N
N
N
N
N
2.1.4. Phenoxy-substituted phthalonitrile 16
The reaction was performed according to the synthesis of 15
described above, using phenol as the second nucleophile. White
crystals, yield (0.62 g, 2.0 mmol, 67%); Rf 0.26 (ethyl acetate/hexane,
2
1
1:2); mp 130e135 ꢁC; [
a
]
D
ꢀ40.9ꢁ (c 0.164, CHCl3); 1H NMR
Fig. 1. Porphyrazines used for comparison purposes.
(300 MHz, CDCl3) dH: 7.44 (2H, t, J ¼ 7.3 Hz), 7.30 (1H, s), 7.27 (1H, d,
J ¼ 7.3 Hz), 7.13 (1H, s), 6.98 (2H, d, J ¼ 7.3 Hz), 4.96 (1H, s), 4.63 (1H,
d, J ¼ 5.9 Hz), 4.60 (1H, d, J ¼ 5.9 Hz), 4.52 (1H, t, J ¼ 7.1 Hz), 4.14 (2H,
m), 3.35 (3H, s), 1.50 (3H, s), 1.27 (3H, s); 13C NMR (75 MHz, CDCl3)
dC: 154.5, 152.4, 151.0, 130.4 (2C), 125.5, 121.8, 119.5 (2C), 117.8, 115.3,
115.1, 112.7, 110.7, 109.7, 109.1, 84.9, 83.6, 81.7, 69.9, 55.3, 26.4, 25,0;
FAB-MS: 422 ([M]þ), 407 ([M ꢀ CH3]þ), 391 ([MeOCH3]þ); IR ymax
(CHCl3)/cmꢀ1: 3051, 2979, 2945, 2937, 2231, 1367, 1199, 1006.
tablets (Fluka) in purified water (Burdick and Jackson or Fluka),
followed by boiling the solution for 5e15 min and cooling to room
temperature. PBS solutions were used within seven days.
Dichlorophthalonitrile 14, octapropylporphyrazine 1, trans-
porphyrazine 2, 3-nitrophthalonitrile 17 and 2,3-dipropylmaleo-
nitrile 30, were prepared according to published procedures
[20e22].
2.1.5. Ribose-derived phthalonitrile 19
2.1. Synthesis
General route for the coupling of carbohydrates to nitro-
phthalonitriles in the presence of NaH as the base: A solution of 1-
2.1.1. Galactosyl/galactosyl disaccharide 8
O-methyl-2,3-O-methylidene-D-ribose (1.20 g, 5.88 mmol) in DMF
Pyranose 7 (800 mg, 1.24 mmol) was dissolved in methanol
(20 mL), to which was then added 10% Pd/C (80 mg) and the
suspension pressurised with hydrogen gas at 350 kPa for 12 h. The
catalyst was filtered off and the product was chromatographed
(hexane/ethyl acetate, 1:1) to give 8 (623 mg, 1.12 mmol, 90%).
(45 mL) was added to 60% NaH (306 mg, 7.64 mmol) at 0 ꢁC. The
reaction mixture was stirred at 0 ꢁC for 30 min after which 3-
nitrophthalonitrile (1.22 g, 7.06 mmol) was added and then stirred at
room temperature for 5 days. The ensuing mixture was poured into
ethyl acetate (600 mL) and washed with water (100 mL ꢂ 3). The
organic layer was dried with MgSO4. After evaporation of the solvent,
the product was purified by flash column chromatography (ethyl
acetate) to yield 19 as white crystals from ethyl acetate (637 mg,
Rf 0.47 (hexane/ethyl acetate, 1:1); 1H NMR (300 MHz, CDCl3) dH
:
5.42 (1H, d, J ¼ 4.5 Hz), 4.86 (3H, m), 4.67 (6H, br s), 4.90 (1H, t,
J ¼ 7.8 Hz), 4.27 (1H, d, J ¼ 7.8 Hz), 4.18 (1H, m), 3.96 (1H, m), 3.90
(1H, s br, OH), 3.60 (4H, m), 3.47 (1H, t, J ¼ 6.6 Hz), 3.34 (6H, s br),
3.33 (3H, s), 1.40 (3H, s), 1.30 (3H, s), 1.23 (6H, s); 13C NMR (75 MHz,
CDCl3) dC: 109.2, 108.9, 103.9, 98.0, 97.3, 96.4, 96.2, 74.9, 74.1, 73.2,
71.2, 70.6, 70.3, 69.4, 67.3, 60.8, 60.2, 55.9, 55.7, 55.6, 25.8 (2C), 24.8,
24.2; FAB-MS: 555 ([M]þ); IR ymax (CHCl3)/cmꢀ1: 3249, 2867, 2801,
1367, 1231.
1.93 mmol, 33%). Rf 0.31 (ethyl acetate); mp 162e167 ꢁC; [
a]
D ꢀ54.6ꢁ
(c 0.218, CHCl3); 1H NMR (300 MHz, CDCl3) dH: 7.57 (1H, t, J ¼ 7.6 Hz),
7.44 (1H, d, J ¼ 7.6 Hz), 7.11 (1H, d, J ¼ 7.6 Hz), 5.06 (1H, s), 4.80 (1H, d,
J ¼ 6.0 Hz), 4.67 (1H, d, J ¼ 6.0 Hz), 4.61 (1H, t, J ¼ 6.3 Hz), 4.21 (2H, d,
J ¼ 6.3 Hz), 3.32 (3H, s), 1.51 (3H, s), 1.33 (3H, s); 13C NMR (75 MHz,
CDCl3) dC: 169.9, 161.5, 155.1, 134.5, 134.3, 118.6, 116.1, 116.0, 112.9,
109.4, 85.1, 84.3, 81.4, 69.4, 55.1, 26.5, 25.0; CI-MS: 333 ([M þ 3]þ), 330
([M]þ), 241 ([MeC4H9O2]þ); IR ymax (CHCl3)/cmꢀ1: 3028, 3018, 2989,
2246, 1367, 1218 1097.
2.1.2. Ribosyl/galactosyl disaccharide 13
The reaction was performed according to that recounted for 8
above. Yield (805 mg, 1.62 mmol, 73%); Rf 0.61 (hexane/acetone,
1:1); 1H NMR (300 MHz, CDCl3) dH: 4.88 (1H, s), 4.83 (2H, m), 4.70
(6H, br s), 4.50 (1H, t, J ¼ 5.7 Hz), 4.28 (2H, m), 3.93 (1H, br s), 3.75
(3H, m), 3.53 (4H, m), 3.74 (6H, s), 3.36 (3H, s), 3.20 (3H, s), 1.41 (3H,
s), 1.25 (3H, s); 13C NMR (75 MHz, CDCl3) dC: 112. 3, 109.1, 103.8,
98.0, 97.5, 96.5, 85.2, 84.9, 82.1, 75.3, 74.5, 73.2, 71.1, 61.0, 56.2, 56.0,
55.8, 54.8, 25.3, 24.8; FAB-MS: 497 ([M ꢀ 1]þ), 467 ([MeOCH3]þ);
IR ymax (CHCl3)/cmꢀ1: 3466, 3019, 2994, 2933, 1339, 1208.
2.1.6. Ribose-derived phthalonitrile 27
White solid, yield (731 mg, 2.21 mmol, 55%); Rf 0.52 (hex-
ane:ethyl acetate, 2:1); mp 123e125 ꢁC; [
a
]
ꢀ37.5ꢁ (c 0.144,
D
CHCl3); 1H NMR (300 MHz, CDCl3) dH: 7.70 (1H, d, J ¼ 8.7 Hz), 7.26
(1H, d, J ¼ 2.4 Hz), 7.20 (1H, dd, J ¼ 8.7 and 2.7 Hz), 5.01 (H1, s), 4.73
(1H, d, J ¼ 5.4 Hz), 4.62 (1H, d, J ¼ 6.0 Hz), 4.51 (1H, t, J ¼ 7.1 Hz),
4.05 (2H, m), 3.32 (3H, s), 1.49 (3H, s), 1.32 (3H, s); 13C NMR
(75 MHz, CDCl3) dC: 161.2, 135.2, 119.4 (2C), 117.5, 116.0, 115.8, 112.8,
109.5, 107.9, 84.9, 83.9, 81.7, 69.3, 55.2, 26.4, 24.9; CI-MS: 315
([M ꢀ CH3]þ), 299 ([MeOCH3]þ); IR ymax (CHCl3)/cmꢀ1: 3081, 2998,
2943, 2231, 1375, 1208, 1023.
2.1.3. Ribose-substituted phthalonitrile 15
A
stirred solution of 4,5-dichlorophthalonitrile (1.60 g,
8.00 mmol) and 1-O-methyl-2,3-O-methylidene-
D
-(ꢀ)-ribose 9
(4.30 g, 21.0 mmol) in dry DMSO (20 mL) was heated to 90 ꢁC. To the
ensuing mixture was added dry, finely powdered potassium
carbonate (3.50 g, 25.0 mmol) in four equal portions over 30 min.
The mixture was stirred at 90 ꢁC for 3 h after which it was poured
into ice-cold water. The precipitate formed was filtered, washed
with water and re-dissolved in ethyl acetate. Evaporation of the
solvent followed by flash silica chromatography (hexane/ethyl
acetate, 1:2) gave compound 15 which was re-crystallised from
methanol (1.17 g, 3.20 mmol, 40%). Rf 0.51 (ethyl acetate/hexane,
2.1.7. Free-base phenoxy-substituted porphyrazine 32
General route to the synthesis of free-base porphyrazines: A
mixture of magnesium (120 mg, 5.00 mmol) and one small crystal
of iodine in n-butanol (80 mL) was heated under reflux for 24 h 2,3-
Dipropylmaleonitrile 30 (1.26 g, 7.77 mmol) and phenoxy-
substituted phthalonitrile 16 (410 mg, 0.971 mmol) were added and
the reaction mixture was heated for an additional 24 h. The mixture
was allowed to cool to room temperature and the solvent was
evaporated under reduced pressure. The crude mixture was dis-
solved in ethyl acetate and filtered to remove impurities. After
evaporation of the solvent, the mixture was partially purified using
1:2); mp 189e192 ꢁC; [
(300 MHz, CDCl3) dH: 7.84 (1H, s), 7.31 (1H, s), 5.08 (1H, s), 4.84 (1H,
d, J ¼ 6.2 Hz), 4.70 (1H, d, J ¼ 6.2 Hz), 4.65 (1H, t, J ¼ 6.2 Hz), 4.19
a
]
D
ꢀ38.3ꢁ (c 0.196, CHCl3); 1H NMR

D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
67
flash column chromatography on silica gel with gradient elution
(hexane/ethyl acetate, 8:1, 3:1, 0:1). Magnesium ion was removed
by overnight treatment of a DCM solution of the mixture with
glacial acetic acid. The resulting blue solution was poured into ice-
cold water (600 mL) and neutralised with an aqueous solution of
sodium hydroxide (1 N). The precipitate that formed was filtered,
washed with water, air dried and dissolved in dichloromethane.
Purification was performed using flash column chromatography on
silica gel (hexane/dichloromethane, 1:1). After evaporation of the
solvent, the product was precipitated from methanol to yield 32 as
a purple solid (207 mg, 0.227 mmol, 23%). Rf 0.14 (dichloro-
methane/hexane, 1:1); mp 169e172 ꢁC; 1H NMR (300 MHz, CDCl3)
dH: 8.74 (1H, s), 8.59 (1H, s), 7.41 (2H, t, J ¼ 7.8 Hz), 7.25 (2H, d,
J ¼ 7.2 Hz), 7.12 (1H, t, J ¼ 7.2 Hz), 5.10 (1H, s), 4.70 (1H, dd, J ¼ 9.0
and 5.4 Hz), 4.61 (1H, d, J ¼ 5.7 Hz), 4.58 (1H, dd, J1 ¼ 9.2 and
5.3 Hz), 4.53 (1H, d, J ¼ 6.0 Hz), 4.38 (1H, t, J ¼ 9.2 Hz), 3.80 (8H, m),
3.69 (4H, m), 3.49 (3H, s), 2.25 (12H, m),1.54 (3H, s) 1.33 (3H, s),1.26
(18H, m), ꢀ3.10 (2H, s); 13C NMR (75 MHz, CDCl3) dC: 161.8, 161.7,
158.9, 157.9, 157.5, 152.5, 146.6, 145.2, 144.9, 144.6, 144.5, 144.2,
143.9, 141.3, 141.2, 140.2139.8, 137.5, 134.3, 129.6 (2C), 122.4, 116.6
(2C), 116.0, 112.3, 109.8, 107.5, 85.2, 84.3, 81.9, 69.5, 55.0, 28.3, 28.1,
27.9 (2C), 26.5 (2C), 25.6 (2C), 25.5 (2C), 25.4 (2C), 25.0 (2C), 14.9
to afford 34 as purple solid (51 mg, 0.052 mmol, 85%). Rf 0.21
(dichloromethane); mp 227e229 ꢁC; 1H NMR (300 MHz, CDCl3) dH
:
8.74 (1H, s), 8.52 (1H, s), 7.39 (2H, t, J ¼ 7.2 Hz), 7.22 (2H, d,
J ¼ 7.8 Hz,), 7.12 (1H, t, J ¼ 7.1 Hz), 5.08 (1H, s), 4.67 (2H, d,
J ¼ 8.7 Hz), 4.59 (1H, d, J ¼ 6.0 Hz), 4.49 (1H, d, J ¼ 6.0 Hz), 4.36 (1H,
t, J ¼ 8.7 Hz), 3.64 (12H, m), 3.48 (3H, s), 2.16 (12H, m), 1.53 (3H, s),
1.31 (3H, s), 1.23 (18H, m); 13C NMR (75 MHz, CDCl3) dC: 158.9 (2C),
152.8 (2C), 149.7, 149.3, 148.1, 147.8 (2C), 147.1, 146.1, 144.6, 144.5,
143.6, 143.4 (2C), 143.0, 135.4, 132.2, 129.7 (2C), 122.6, 116.8 (2C),
115.3, 112.4, 109.8, 106.3, 85.2, 84.2, 81.9, 69.4, 54.9, 29.7, 28.1 (3C),
27.9, 26.4, 25.5 (3C), 25.3, 25.2, 24.9, 14.8 (6C); UVevis (CHCl3) lmax
(log 3
): 597 (4.38), 297 (4.38), 248 (4.35); FAB-MS: 968 ([M]þ).
2.1.10. Free-base ribose-substituted porphyrazine 36
Chromatographed (hexane/dichloromethane, 2:3), purple solid
(161 mg, 0.197 mmol, 23%); Rf 0.25 (hexane/dichloromethane, 2:3);
mp 158e160 ꢁC; 1H NMR (300 MHz, CDCl3) dH: 8.91 (1H, d,
J ¼ 6.9 Hz), 7.97 (1H, t, J ¼ 7.7 Hz), 7.52 (1H, d, J ¼ 8.1 Hz), 5.28 (1H, d,
J ¼ 5.7 Hz), 5.18 (1H, s), 4.82 (1H, d, J ¼ 6.0 Hz), 4.73 (1H, m), 4.27
(2H, m), 3.97 (8H, m), 3.78 (4H, m), 3.46 (3H, s), 2.34 (12H, m), 1.61
(3H, s), 1.41 (3H, s), 1.26 (18H, m), ꢀ2.33 (2H, s); 13C NMR (75 MHz,
CDCl3) dC: 162.5, 162.2, 158.8, 158.7, 155.2 (2C), 145.7, 145.6, 144.9,
144.8, 143.4, 141.7, 141.5, 141.1, 140.6, 130.8, 127.3, 116.2, 114.3, 112.5,
109.7, 85.4, 84.9, 82.7, 70.1, 55.2, 29.8 (2C), 28.3, 28.2, 28.1, 28.0,
27.8, 26.6, 25.5, 25.4 (2C), 25.3, 25.3, 25.1, 14.8 (3C), 14.7 (2C), 14.6;
(3C), 14.8 (3C); UVevis (CHCl3) lmax (log 3): 649 (5.09), 620 (4.04),
572 (5.05), 346 (5.13); FAB-MS: 910 ([M ꢀ 1]þ).
2.1.8. Zinc-containing phenoxy-substituted porphyrazine 33
UVevis (CHCl3) lmax (log 3): 654 (4.68), 577 (4.12), 327 (4.51); FAB-
General route for the metalation of porphyrazines with zinc: For
MS: 819 ([M]þ), 788 ([MeOCH3]þ).
33: To
a solution of the free-base porphyrazine (70 mg,
0.077 mmol) in chlorobenzene (50 mL) and DMF (3 mL) was added
Zn(OAc)2$2H2O (30 mg, 0.14 mmol). The mixture was heated to
reflux overnight, after which it was cooled to room temperature
and poured into ethyl acetate (300 mL). The reddish-purple solu-
tion was washed with water (100 mL ꢂ 3) and dried over anhydrous
MgSO4. After evaporation of the solvent, purification was per-
formed using flash column chromatography by loading the sample
onto the column with a dichloromethane/hexane mixture (1:1)
followed by elution with dichloromethane/tetrahydrofuran (5:1).
Further purification was achieved by precipitation of the metalated
product from dichloromethane/methanol (63 mg, 0.065 mmol,
84%). Rf 0.33 (hexane/tetrahydrofuran, 1:10); mp 237e242 ꢁC; 1H
NMR (300 MHz, CDCl3) dH: 8.84 (1H, s), 8.56 (1H, s), 7.38 (2H, t,
J ¼ 7.3 Hz), 7.21 (2H, d, J ¼ 7.8 Hz), 7.09 (1H, t, J ¼ 7.2 Hz), 4.83 (1H,
s), 4.46 (1H, d, J ¼ 6.0 Hz), 4.43 (2H, d, J ¼ 10.5 Hz), 4.37 (1H, d,
J ¼ 6.0 Hz), 4.26 (1H, t, J ¼ 10.4 Hz), 3.58 (12H, m), 3.36 (3H, s), 2.12
(12H, m), 1.49 (3H, s), 1.43 (3H, s), 1.20 (18H, m); 13C NMR (75 MHz,
CDCl3) dC: 158.7, 157.3, 156.8, 155.3, 155.1, 154.8, 152.9, 152.5, 152.4,
146.8, 144.3, 144.2, 144.1, 143.3, 143.2, 142.9, 142.4136.2, 133.0, 129.6
(2C), 122.4, 116.7 (2C), 115.9, 112.2, 109.5, 107.1, 85.0, 84.1, 81.7, 69.3,
54.8, 28.2, 28.0, 26.4 (2C), 25.6 (2C), 25.5 (2C), 25.4 (2C), 24.8 (2C),
2.1.11. Zinc-containing ribose-substituted porphyrazine 40
Chromatographed (hexane/acetone, 5:1), (52 mg, 0.059 mmol,
75%); Rf 0.16 (hexane/acetone, 5:1); mp 154e156 ꢁC; 1H NMR
(300 MHz, CDCl3) dH: 8.69 (1H, d, J ¼ 6.9 Hz), 7.88 (1H, t, J ¼ 7.5 Hz),
7.32 (1H, d, J ¼ 7.8 Hz), 5.00 (1H, d, J ¼ 5.4 Hz), 4.77 (1H, s), 4.71 (1H,
t, J ¼ 6.6 Hz), 4.59 (1H, d, J ¼ 5.7 Hz), 4.41 (2H, d, J ¼ 6.9 Hz), 3.78
(2H, m), 3.61 (6H, m), 3.43 (4H, s), 3.26 (3H, s), 2.21 (6H, m), 2.07
(6H, m), 1.49 (3H, s), 1.27 (9H, m), 1.25 (3H, m), 1.16 (9H, m); 13C
NMR (75 MHz, CDCl3) dC: 158.1, 157.9, 156.5, 156.3, 155.2, 153.7,
153.6145.4, 144.3, 143.3, 143.1, 142.7, 141.9 (2C), 140.6, 130.3, 126.3,
116.1, 113.6, 112.6, 109.5, 85.1, 84.8, 82.3, 77.2, 69.9, 54.9, 29.6, 29.3,
28.4, 28.1, 27.9, 27.7, 27.0, 26.4, 25.5, 25.4, 25.3, 25.0, 24.9, 22.6, 14.9,
14.8 (2C), 14.7 (2C), 1.41; UVevis (CHCl3) lmax (log 3): 617 (4.18), 343
(5.01), 264 (4.58); FAB-MS: 882 ([M]þ).
2.1.12. Nickel-containing ribose-substituted porphyrazine 44
Chromatographic purification was performed using hexane/
ethyl acetate (1:1), (60 mg, 0.069 mmol, 87%); Rf 0.15 (hexane/
dichloromethane, 1:1); mp 169e173 ꢁC; 1H NMR (300 MHz, CDCl3)
dH: 8.69 (1H, d, J ¼ 7.5 Hz), 7. 90 (1H, t, J ¼ 7.7 Hz), 7.43 (1H, d,
J ¼ 8.1 Hz), 5.23 (1H, d, J ¼ 5.7 Hz), 5.17 (1H, s), 5.15 (1H, t,
J ¼ 5.7 Hz), 4.81 (1H, d, J ¼ 5.7 Hz), 4.65 (2H, m), 3.99 (1H, m), 3.68
(7H, m), 3.49 (4H, m), 3.47 (3H, s), 2.28 (6H, m), 2.11 (6H, m), 1.65
22.7 (2C), 15.0 (3C), 14.9 (3C); UVevis (CHCl3) lmax (log 3): 610
(4.00), 345 (4.13), 266 (3.71); FAB-MS: 974 ([M]þ).
(3H, s), 1.41 (3H, s), 1.23 (18H, m); 13C NMR (75 MHz, CDCl3) dC
:
2.1.9. Nickel-containing phenoxy-substituted porphyrazine 34
154.8, 149.7, 149.2, 148.0, 147.9,147.8, 147.7, 146.2, 146.1, 144.3, 144.2,
144.0, 143.4, 143.3, 142.9, 140.6, 130.2, 125.2, 115.2, 113.0, 112.6,
109.8, 85.4, 84.8, 82.8, 77.2, 69.8, 55.1, 29.6, 28.3, 28.0, 27.9, 27.8,
27.7, 27.6, 26.5, 25.5, 25.4, 25.3, 25.2 (2C), 25.0, 24.9, 14.9, 14.8 (2C),
General route to metalation of porphyrazines with nickel: For
34: The free-base porphyrazine (55 mg, 0.061 mmol) was dissolved
in chlorobenzene (30 mL). This was followed by addition of dry
DMF (3 mL) and Ni(OAc)2$4H2O (26 mg, 0.11 mmol). The mixture
was heated under reflux for 14 h, cooled to room temperature and
poured into ethyl acetate (250 mL). The reddish-purple solution
was washed with water (50 mL ꢂ 3) and dried over anhydrous
MgSO4. After evaporation of the solvent, purification was carried
out using flash column chromatography by washing the sample
onto the column with dichloromethane/hexane (1:1) followed by
elution with neat dichloromethane. The product was precipitated
from dichloromethane/pentane as a means of further purification
14.7 (2C), 14.6; UVevis (CHCl3) lmax (log 3): 604 (4.65), 315 (4.44),
291 (4.36); FAB-MS: 876 ([M]þ).
2.1.13. Free-base ribose-substituted porphyrazine 49
Chromatographed (hexane/dichloromethane 1:3), purple solid
(356 mg, 0.435 mmol, 26%); Rf 0.31 (hexane/dichoromethane, 1:3);
mp 223e229 ꢁC; 1H NMR (300 MHz, CDCl3) dH: 8.84 (1H, J ¼ 8.1 Hz,
d), 8.44 (1H, s), 7.52 (1H, d, J ¼ 8.1 Hz), 5.18 (1H, s), 5.07 (1H, d,
J ¼ 6.0 Hz), 4.84 (1H, m), 4.48 (1H, d, J ¼ 5.7 Hz), 4.50 (1H, t,

68
D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
J ¼ 9.0 Hz), 4.41 (1H, t, J ¼ 8.4 Hz), 3.83 (8H, m), 3.69 (4H, m), 3.53
(3H, s), 2.23 (12H, m), 1.63 (3H, s), 1.45 (3H, s), 1.26 (18H, m), ꢀ2.68
(2H, s); 13C NMR (75 MHz, CDCl3) dC: 161.9, 161.6, 160.4, 158.9, 158.1,
145.7, 145.1, 144.6, 144.5, 144.4, 144.0, 142.3, 141.4, 141.3, 140.2,
139.9, 133.7, 123.4, 117.0, 112.7, 109.5, 106.8, 85.3, 84.9, 82.3, 69.1,
55.1, 29.8, 28.3, 28.1, 27.9, 26.6 (2C), 25.6 (2C), 25.5 (2C), 25.4 (2C),
0.044 mmol, 77%). Rf 0.29 (hexane/dichloromethane, 3:1), mp
186e190 ꢁC; 1H NMR (300 MHz, CDCl3) dH: 8.95 (1H, d, J ¼ 7.5 Hz),
8.02 (1H, t, J ¼ 7.7 Hz), 7.67 (1H, d, J ¼ 7.8 Hz), 6.32 (1H, d, J ¼ 3.9 Hz),
5.66 (1H, d, J ¼ 3.3 Hz), 5.02 (2H, m), 4.72 (1H, dd, J ¼ 7.4 and
3.2 Hz), 4.11 (2H, m), 3.94 (12H, m), 2.30 (12H, m), 1.66 (3H, s), 1.54
(2H, s br), 1.36 (3H, s), 1.25 (18H, m), ꢀ2.25 (2H, s): 13C NMR
(75 MHz, CDCl3) dC: 163.1, 162.3, 158.3, 158.0, 153,1 145.6, 145.3,
145.2 (2C), 144.9, 144.4, 143.6, 141.9, 141.7, 140.9, 140.8, 130.9, 127.4,
116.6, 113.7, 112.3, 105.6, 82.7, 81.6, 79.8, 69.8, 64.8, 29.7 (3C), 29.4,
28.3, 28.0, 27.9, 27.4, 26.9, 26.4, 25.6 (2C), 25.5, 25.3, 14.9 (2C), 14.8
25.2 (2C), 14.9 (3C), 14.8 (2C); UVevis (CHCl3) lmax (log 3): 652
(5.23), 568 (4.96), 346 (5.02); FAB-MS: 819 ([M]þ).
2.1.14. Zinc-containing ribose-substituted porphyrazine 54
Chromatographed using tetrahydrofuran/dichloromethane
(1:7), purple solid (69 mg, 0.078 mmol, 75%); Rf 0.29 (hexane/
tetrahydrofuran, 6:1); mp 244e247 ꢁC; 1H NMR (300 MHz, pyri-
dine-d5) dH: 9.61 (1H, d, J ¼ 8.1 Hz), 9.32 (1H, s), 7.96 (1H, d,
J ¼ 8.1 Hz), 5.39 (1H, s), 5.14 (1H, d, J ¼ 6.0 Hz), 5.08 (1H, m), 4.97
(1H, d, J ¼ 5.7 Hz), 4.67 (2H, m), 4.13 (12H, m), 3.49 (3H, s), 2.56
(12H, m), 1.65 (3H, s), 1.44 (3H, s), 1.36 (18H, m), 13C NMR (75 MHz,
pyridine-d5) dC: 161.3, 159.8, 159.3, 157.7, 157.5, 157.3, 157.2, 156.0,
155.4, 144.8, 144.7, 143.7, 143.5, 143.4, 143.2, 142.4, 133.7, 124.6,
118.3, 112.7, 110.0, 107.7, 85.9, 85.3, 82.7, 70.2, 54.9, 30.0, 28.8, 28.6
(2C), 26.8 (2C), 26.3 (2C), 26.2 (2C), 26.1 (2C), 25.1 (2C), 15.2 (3C),
(2C), 14.3, 14.2; UVevis (2-Octanol) lmax (log 3): 655 (5.10), 577
(5.05), 327 (4.97); FAB-MS: 835 ([M]þ).
2.2. Measurement of partition coefficients
A typical experiment was performed as follows: The porphyr-
azine derivative (7 mg) was dissolved in 2-octanol (10 mL), which
was stirred at room temperature for 12 h. The solution was filtered
using a sintered glass funnel, to remove any undissolved porphyr-
azine. This was followed by addition of PBS solution (10 mL) and the
mixture was stirred for the next 8e12 h. The two layers were
allowed to separate (3 min). Aliquots of the aqueous (10 mL) and
organic layers (0.5e2 mL), were taken. The aqueous layer was
diluted to 20 mL with 2.0 M solution of HCl in THF. The organic layer
was treated with PBS (8e9.5 mL) and then diluted to 40e70 mL
with a 2.0 M solution of HCl in THF. Electronic spectra were
measured (300e700 nm), using 1 cm path length glass cuvettes.
The absorbances were taken from the Soret band region as well as
the red band region. The partition coefficients were calculated
using equation (4). The measurements were carried out in
triplicate.
15.1 (3C); UVevis (CHCl3) lmax (log 3): 609 (4.78), 343 (5.01), 264
(4.58); FAB-MS: 882 ([M]þ).
2.1.15. Nickel-containing ribose-substituted porphyrazine 57
Chromatographed using dichloromethane, purple solid (49 mg,
0.055 mmol, 64%); Rf 0.64 (dichloromethane); mp 237e240 ꢁC; 1H
NMR (300 MHz, chlorobenzene-d5, 50 ꢁC) dH
: 9.06 (1H, d,
J ¼ 8.1 Hz), 8.58 (1H, s), 7.36 (1H, d, J ¼ 8.1 Hz), 4.91 (1H, s), 4.70 (1H,
d, J ¼ 6.3 Hz), 4.63 (1H, t, J ¼ 6.5 Hz), 4.50 (1H, d, J ¼ 6.0 Hz), 4.21
(1H, t, J ¼ 6.0 Hz), 4.19 (1H, t, J ¼ 6.6 Hz), 3.65 (12H, m), 3.17 (3H, s),
2.17 (12H, m), 1.32 (3H, s), 1.14 (3H, s), 1.11 (18H, m); 13C NMR
75 MHz, Chlorobenzene-d5, 50 ꢁC) dC: 160.5 (2C), 148.4 (2C), 147.9,
144.9 (2C), 143.7 (2C), 143.5 (2C), 123.8, 118.3, 112.8, 109.7, 105.5,
85.3, 84.9, 82.3, 69.2, 55.0, 28.2 (2C), 26.6 (6C), 25.5 (3C), 25.1 (3C),
3. Results and discussion
3.1. Carbohydrate synthesis
14.8 (6C); UVevis (CHCl3) lmax (log
3): 598 (4.62), 293 (4.46); FAB-
MS: 874 ([M ꢀ 2]þ)
For the purpose of this study, any protecting groups on the
carbohydrate would have to be base-stable in order to withstand
the Linstead macrocyclisation conditions (Mg(OBu)2, n-BuOH,
reflux). Several protecting groups, such as acetals, show this base-
resistance and were therefore deemed suitable for our purposes
[23]. Accordingly, acetonide-protected D-(ꢀ)-ribose 9 was used in
coupling reactions with phthalonitriles as described below.
Disaccharides were also of interest for this study but there are
limited numbers and types of commercially available disaccharides.
In the present study, it was important to be able to prepare disac-
charides such that (i) one hydroxyl group remained unmasked or
could be selectively deprotected and (ii) the protecting groups
would be resistant to the Linstead macrocyclisation conditions.
2.1.16. Deprotected phenoxy-substituted porphyrazine 61
General route for the isopropylidene-deprotection of free-base
porphyrazines using methanol: For 61, 32 (42 mg, 0.042 mmol) was
dissolved in THF (25 mL), followed by the addition of MeOH (5 mL)
and a catalytic amount of p-TsOH. The ensuing reaction mixture
was heated to 75e78 ꢁC for 48 h (TLC monitoring), after which the
mixture was quenched by cooling to room temperature. The crude
product was dissolved in ethyl acetate (200 mL), washed succes-
sively with an aqueous sodium hydrogen carbonate solution
(20 mL ꢂ 3), water (20 mL ꢂ 3), dried with MgSO4 and concen-
trated. Flash chromatography (hexane/ethyl acetate, 2:1) followed
by precipitation (hexane/ethyl acetate) gave (14 mg, 0.016 mmol,
36%). Rf 0.15 (hexane/ethyl acetate, 2:1); mp 232e238 ꢁC; UVevis
1:2,3:4-Di-O-isopropylidene- -galactopyranose 4 was selected as
D
a suitable commercially available starting material. Disaccharide
synthesis was carried out as shown in Scheme 1, following several
protection/deprotection steps and other functional group
transformations.
(2-Octanol) lmax (log 3): 670 (4.90), 600 (4.86), 580 (4.79), 390
(4.84); MS-FAB: 870.0 ([M þ 1]þ).
2.1.17. Deprotected glucose-substituted porphyrazine 62
The disaccharides were synthesised by using galactosyl bromide
3 [24] as the glycosyl donor and 4 or 9 as the glycosyl acceptor, in
the presence of Ag2CO3 and molecular sieves. The products 5 and
10, respectively, were purified and deprotected of their acetyl
groups using triethylamine in methanol at 40 ꢁC. MOM protection
(to provide base-stable groups referred to earlier) of the partially
protected disaccharides 6 or 11 with chloromethyl methyl ether in
the presence of a base (Scheme 2) afforded the desired products 7
and 12 in yields of 90% and 88%, respectively. Removal of the benzyl
group by hydrogenolysis (10% Pd/C, 350 kPa hydrogen pressure)
finally yielded the disaccharides 8 (91%) or 13 (73%) with one free
General route to the isopropylidene-deprotection of free-base
porphyrazines using methanol and water: For 62, to a stirred
solution of 36 (50 mg, 0.057 mmol) in THF (40 mL) was added
MeOH/H2O (2 mL:1.5 mL) and a catalytic amount of p-TsOH. The
mixture was heated to 50e55 ꢁC overnight, after which it was
poured into ethyl acetate (300 mL) and neutralised with an
aqueous sodium hydrogen carbonate solution (20 mL ꢂ 3). It was
washed with water (20 mL ꢂ 3), dried with MgSO4 and concen-
trated. Chromatographic separation (hexane/ethyl acetate, 3:1)
followed by precipitation (DCM/MeOH) yielded 62 (37 mg,

D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
69
BnO
AcO
NC
NC
NC
O
Br
NC
O
AcO OAc
3
HO
O
O
O
O
OMe
HO
O
O
OMe
O
O
O
O
19
O
O
O O
O
O
O
O
Ag2CO3
DCM
Ag2CO3
DCM
4
18
9
R'O
RO
RO OR
R'O
RO
RO OR
4, K CO , DMF
rt, 57%
9, NaH, DMF
2
3
O
O
O
rt, 33%
O
O
OMe
i
O
O
O
NC
NC
O
O
O
O
NH2
N
N
NO
17
2
5: R = Ac, R' = Bn
6: R = H, R' = Bn
7: R = MOM, R' = Bn
8: R = MOM, R' = H
10: R = Ac, R' = Bn
11: R = H, R' = Bn
12: R = MOM, R' = Bn
13: R = MOM, R' = H
i
O
O
O
ii
ii
H
N
HO
O
O
iii
iii
HO
K CO
DMF
2
3
22
20
O
O
O
O
Scheme 1. Synthesis of disaccharide carbohydrates. i) Et3N, MeOH, 40 ꢁC; ii) NaH, THF,
MOMCl; iiii) Pd/C, H2, MeOH.
NaH, DMF
rt, 80%
rt, 71%
NC
NC
NH
2
O
O
N
N
NC
NC
N
hydroxyl group, which could be used in coupling reactions with the
phthalonitrile.
N
O
O
H
O
O
O
21
3.2. Phthalonitrile synthesis
O
23
4,5-Dichlorophthalonitrile 14 was coupled with protected
ribose 9 in the presence of potassium carbonate in DMSO to give
compound 15 in 40% yield (Scheme 2).
Scheme 3. Synthesis of 3-carbohydrate-functionalised phthalonitriles.
Even though 2 equivalents of carbohydrate were used in the
reaction, only the mono carbohydrate-substituted phthalonitrile 15
was obtained in moderate yield even after prolonged heating. It is
probable that the second substitution failed due to steric hindrance.
The product was crystallised from DCM by trituration with meth-
anol and was collected as white needle-shaped crystals. Despite the
lack of reactivity in the presence of an excess of 9, product 15 could
be made to react with phenol to afford compound 16 as white
crystals after crystallisation from DCM by trituration with MeOH. A
reversal of this coupling reaction afforded only the diphenoxy
substituted phthalonitrile.
The use of a nitro moiety as a leaving group on a phthalonitrile
substrate required different conditions compared to the use of
chloro leaving groups, as was established after some experimen-
tation. Four different functionalised carbohydrates, namely 4, 9, 20
and 22, were coupled with phthalonitrile 17 using NaH or K2CO3 as
base in DMF to give the corresponding phthalonitrile adducts 18
(33%, NaH as base), 19 (57%, K2CO3 as base), 21 (71%, K2CO3 as base)
and 23 (80%), respectively (Scheme 3). Presumably, the free amine
of 22 fails to react with the otherwise susceptible nitro-
phthalonitrile substrate (17, here, and 24, below) due to its signif-
icantly lowered nucleophilicity, it being an aromatic amine on an
aromatic heterocycle. It is in all likelihood the same reasoning that
accounts for the absence of amidine formation during the macro-
cyclisation reactions of products 23 and 26, the reactions of which
are detailed below in Schemes 6 and 7, to produce macrocyclic
structures 38, 42, 46, 48, 53 and 56, respectively.
Functionalisation of 24 with each of five carbohydrate deriva-
tives was achieved through the use of selectively protected carbo-
hydrates with primary hydroxyl groups as nucleophiles to afford
the various products in moderate yields (18e66%). In each coupling
reaction, the phthalonitrile was added to a suspension of the
carbohydrate and potassium carbonate in DMF (Scheme 4) to
provide products 25 (52%), 26 (52%), 27 (55%), 28 (48%) and 29
(79%) as pure products after column chromatography. The large
difference in the yields for 28 and 29, which are structurally similar
products, is not understood but was consistently observed through
several repeat reactions.
NC
NC
Cl
O
3.3. Synthesis, deprotection and metalation of porphyrazines
9, K2CO3
NC
NC
Cl
Cl
O
OMe
DMSO
In the synthesis of the functionalised porphyrazines (Schemes
6e8), 8e15 equivalents of 2,3-dipropylmaleonitrile 30 were reac-
ted with each carbohydrate-substituted phthalonitrile (1 equiva-
lent), respectively, by heating each mixture under reflux in
n-butanol in the presence of Mg(OBu)2 for 24 h. The magnesium-
complexed product obtained from each reaction was partially
purified by flash column chromatography using hexane/ethyl
acetate mixtures as the eluent to afford reddish-blue Mg-com-
plexed products at >80% purity. Removal of the central magnesium
ion was effected using glacial acetic acid at room temperature by
dissolving each porphyrazine in DCM followed by the addition of
15
14
O
O
K2CO3
DMSO
OH
NC
NC
O
O
O
OMe
16
O
O
Scheme 2. Selective functionalisation of 4,5-dichlorophthalonitrile.

70
D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
Similarly, free-base porphyrazines 35e38, shown in Scheme 6,
CN
CN
O
NC
NH2
N
N
were prepared by reaction of 6e8 equivalents of 30 with each
carbohydrate-substituted phthalonitrile 18, 19, 21 and 23, respec-
tively. After removal of the central metal ion, the products were
precipitated from methanol and collected as blue precipitates to
yield 35 (23%), 36 (37%), 37 (12%) and 38 (30%).
NC
N
N
O
O
O
O
25
26
O
O
O
O
O
Metalation of free-base pigments 35e38 with Zn(OAc)2$2H2O or
Ni(OAc)2$4H2O afforded metalated porphyrazines 39e46 (Scheme
6). Precipitation of the complexes from appropriate solvents
proved the method of choice to provide analytically pure products.
Lower yields were obtained for both 39 and 43, which were syn-
thesised from 35. Both of these compounds easily decomposed
during evaporation of the solvent and also under conditions under
which they were synthesised. When the metal insertion was
carried out at temperatures between 70 ꢁC and 100 ꢁC, the yields
were lower than 50% due to incomplete conversion of the substrate
to product. At higher temperatures, the products decomposed.
Pigments 47e51 were similarly prepared (Scheme 7) and puri-
fied by chromatography and precipitation from methanol (47, 26%;
48; 28%; 49; 18%; 50, 8%; 51, 22%). The low yield of 50 resulted due
to the dipropylmaleonitrile being consumed faster than the
phthalonitrile derivative, because of their differential reactivity,
resulting in less of the dipropylmaleonitrile coupling with the
phthalonitrile adduct.
4
K2CO3
DMF, rt, 52%
22, K2CO3, DMF
rt, 56%
NC
NaH, rt
DMF, 55%
NC
NO2
CN
24
CN
O
9
13, NaH, DMF, rt, 18%
O
OMe
O
O
NC
O
O
NC
MOMO
O
O
OMe
27
MOMO OMOM
28
NaH, DMF
, rt, 79%
O
O
8
NC
O
O
NC MOMO
O
O
O
The zinc- and nickel-metalated derivatives of 47e49 were
prepared from the metal acetate salts using the protocols described
above, to provide 52 (81%), 53 (51%), 54 (75%), 55 (64%), 56 (63%)
and 57 (63%). Precipitation was again most useful approach to assist
in purification of the materials. With complex 56, precipitation was
MOMO OMOM
O
O
O
29
Scheme 4. Synthesis of 4-carbohydrate-functionalised phthalonitriles.
acetic acid, and the reaction mixture was stirred overnight. Chro-
matography provided the pure free-base macrocycles.
The porphyrazines of this study were metalated with both
nickel and zinc by reaction thereof for 16 h with the metal acetate
salts in a mixture of chlorobenzene and DMF, the ratio of which
depended on the porphyrazine solubility in chlorobenzene. At
temperatures of about 100 ꢁC or lower, products were obtained in
low yields (i.e., <50%), the consequence of which is that the reac-
tions were performed at temperatures above 100 ꢁC. The por-
phyrazine complexes could be purified by column chromatography,
which was sometimes complicated due to the low solubility of the
nickel complexes in most organic solvents.
Reaction of 8 equivalents of maleonitrile 30 with 16 gave the
magnesium complex 31 which was partially purified by chroma-
tography (Scheme 5). Further manipulations as described above
provided 32 (M ¼ 2H, 23%, blue amorphous solid), 33 (M ¼ Zn, 84%,
red-purple amorphous solid) and 34 (M ¼ Ni, 85%, red-purple
amorphous solid).
i) Mg(OBu)2
reflux, n-BuOH
N
N
N
ii) HOAc, DCM
N M N
N
+
30 18/19/21/23
iii) Zn(OAc)2
or
Ni(OAc)2
PhCl, DMF
N
N
R
35-46
O
O
O
O
OMe
18: R =
19: R =
O
O
O
O
O
O
NH2
N
N
O
N
N
O
H
O
23: R =
21: R =
O
O
O
O
O
O
O
i) 16, Mg(OBu)
2
reflux, n-BuOH
ii) HOAc, DCM
35: M = 2H, R = as for 18 (30%)
36: M = 2H, R = as for 19 (23%)
37: M = 2H, R = as for 21 (37%)
38: M = 2H, R = as for 23 (12%)
39: M = Zn, R = as for 18 (29%)
40: M = Zn, R = as for 19 (75%)
41: M = Zn, R = as for 21 (84%)
42: M = Zn, R = as for 23 (59%)
43: M = Ni, R = as for 18 (25%)
44: M = Ni, R = as for 19 (87%)
45: M = Ni, R = as for 21 (86%)
46: M = Ni, R = as for 23 (66%)
N
N
N
OPh
O
N M N
iii) Zn(OAc)
2
N
NC CN
30
N
N
OMe
O
or
Ni(OAc)
2
O
O
PhCl, DMF
31: M = Mg
32: M = 2H
33: M = Zn
34: M = Ni
ii
iii
Scheme 5. Synthesis of ribose-derived porphyrazine.
Scheme 6. Synthesis of carbohydrate-functionalised porphyrazines.

D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
71
i) Mg(OBu)
2
reflux, n-BuOH
ii) HOAc, DCM
N
N
N
p-TsOH, MeOH/H2O
or p-TsOH, MeOH
N
N
N
R3
R2
N M
N
N
+ 25/26/27/28/29
30
32/36/47/49
N M N
N
R
iii) Zn(OAc)
or
2
THF
N
N
R1
N
N
Ni(OAc)
2
PhCl, DMF
47-57
NH
N
N
2
61-65
N
N
61: R1 = H, R2 = OPh, R3 =
O
25: R =
O
O
O
OMe
HO
HO
(36%)
O
26: R =
O
O
O
O
O
HO OH
H
O
O
O
O
62: R2 = R3 = H, R1 = O
27: R =
O
O
28: R = O
O
OMe
(77%)
O
HO
HO
H
O
O
O
MOMO
O
OMe
MOMO OMOM
O
O
O
63: R2 = R3 = H, R1 =
O
29: R =
O
OH
OH
O
(58%)
MOMO
O
O
64: R1 = R3 = H, R2 =
MOMO OMOM
O
O
O
O
O
O
(63%)
HO
OH
OH
65: R1 = R3 = H, R2 =
HO
O
O
OMe
(73%)
47: M = 2H, R = 25 (28%)
48: M = 2H, R = 26 (8%)
49: M = 2H, R = 27 (26%)
50: M = 2H, R = 28 (18%)
51: M = 2H, R = 29 (22%)
52: M = Zn, R = 25 (81%)
53: M = Zn, R = 26 (51%)
54: M = Zn, R = 27 (75%)
55: M = Ni, R = 25 (64%)
56: M = Ni, R = 26 (63%)
57: M = Ni, R = 27 (64%)
HO OH
Scheme 8. Deprotection of carbohydrate-functionalised porphyrazines.
at m/z 835.4 ([M]þ), for 63 at m/z 796 ([M þ 1]þ), for 64 at m/z 796
([M þ 1]þ) and for 65 at m/z 779 ([M]þ), all of which were the
anticipated signals.
In the case of porphyrazine 32, this material was protected by
a methyl and an isopropylidene acetal on the D-(ꢀ)-ribose residue.
Both of these groups are potentially cleavable under acidic condi-
tions. To prevent mixtures of partially and fully deprotected prod-
ucts, neat MeOH was used instead of using aqueous methanol, as
shown in Scheme 8. This approach very effectively ensured reten-
tion of the 1-O-methyl protecting group when heating for two days
at 75e78 ꢁC. The diol product 61, which was precipitated from
a mixture of hexane and ethyl acetate, was collected as a purple
precipitate in 36% yield.
Compound 36 was selectively deprotected by heating a mixture
thereof in THF/MeOH/H2O (40:2:1.5, v/v/v) and p-TsOH at 50e55 ꢁC
for 12e14 h to give 62, which was collected in 77% yield as a blue
precipitate from methanol. Raising the temperature to 75 ꢁC
allowed deprotection of the second isopropylidene acetal to give 63
as a mixture, after running the reaction for up to three days, with
small amounts of 62 remaining. Deprotected porphyrazine 63 was
collected as blue precipitate in 58% after treatment of pigment 62
with p-TsOH in aqueous MeOH. For diol 62, disappearance of only
two of the four high-field methyl singlet signals in the 1H NMR
spectrum of the product clearly indicated the removal of one iso-
propylidene acetal group only.
Scheme 7. Synthesis of carbohydrate-functionalised porphyrazines.
carried out using methanol, but this macrocycle was virtually
insoluble in every organic solvent.
As one of the objectives of this study, deprotection of the syn-
thesised porphyrazines was to be performed. Deprotection of the
carbohydrate-functionalised compounds was anticipated to
increase their solubility in aqueous media. The deprotection
transformation of compounds 32, 36, 47 and 49 (Scheme 8) in
aqueous- or in neat methanol, depending on the desired selectivity
for the group to be deprotected, was effected using p-TsOH (p-tol-
uenesulfonic acid). Each porphyrazine was dissolved in a suitable
amount of THF, followed by addition of neat MeOH or aqueous
MeOH and the sulfonic acid and the mixture was then heated.
Deprotection was performed at elevated temperatures since no
deprotection at all was observed at room temperature even after
extended periods of time, which may relate to the solubility of the
parent compounds in the reaction mixture. The temperature was
found to be critical for each reaction such that a slight increase or
decrease of the temperature negatively affected the yield. Por-
phyrazines 61e65, all of which were cleaved of their isopropylidene
acetal protecting groups, were poorly soluble in all solvents tested
and could therefore not be characterised using NMR spectroscopy
(but for 62).
Compound 47 was treated with MeOH/H2O (1:1 v/v) for three to
four days in the presence of p-TsOH. The product 64 was collected
in 63% yield after precipitation from DCM. For this reaction, the
temperature was controlled at 75e80 ꢁC. Heating the mixture at
temperatures outside of this range lowered the yield or failed
altogether to effect any reaction at all. Compound 64 was collected
as a mixture of anomers, as is expected for a free sugar which is
The nature of the insoluble products was tentatively confirmed
by FAB-MS (low resolution) which showed the expected molecular
ion peaks. Gratifyingly, compound 62 was fairly soluble and could
be analysed using FAB-MS, 1H NMR and 13C NMR spectroscopy.
FAB-MS analysis exhibited peaks for 61 at m/z 870 ([M ꢀ 1]þ), for 62
present as a mixture of a and b isomers. In a similar way, compound
65 could be obtained from its parent molecule 49 in a yield of 73%
yield after precipitation from DCM.

72
D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
Table 1
3.4. Electronic absorption spectra
Partition coefficients of porphyrazines.
C(M)1a
K2ow
b
The UVevisible spectra for the free-base porphyrazines in the
present study demonstrate generic Soret and Q-Band features
strongly resembling those of unsymmetrical porphyrazine or
phthalocyanine analogues. Porphyrazines 32, 35e38, 47e51 and
61e65, which are all free-base porphyrazines, exhibit Soret
absorption maxima between 325 and 348 nm and a split Q-band,
having Qx and Qy absorbances at 571e580 nm and 649e656 nm,
which is distinctive of unsymmetrical (D2h symmetry) free-base
tetraazaporphyrins. Gouterman’s simplified four molecular orbital
Compound
1
2
9.427 ꢂ 10ꢀ3
8.821 ꢂ 10ꢀ3
5.488 ꢂ 10ꢀ3
5.714 ꢂ 10ꢀ3
6.104 ꢂ 10ꢀ3
5.714 ꢂ 10ꢀ3
5.422 ꢂ 10ꢀ3
5.714 ꢂ 10ꢀ3
5.422 ꢂ 10ꢀ3
6.104 ꢂ 10ꢀ3
5.422 ꢂ 10ꢀ3
5.986 ꢂ 10ꢀ3
4.592 ꢂ 10ꢀ3
4.711 ꢂ 10ꢀ3
5.032 ꢂ 10ꢀ3
5.032 ꢂ 10ꢀ3
4.884 ꢂ 10ꢀ3
1.21 ꢂ 104
1.01 ꢂ 104
1.74 ꢂ 103
1.61 ꢂ 103
4.35 ꢂ 103
1.27 ꢂ 103
1.26 ꢂ 103
1.75 ꢂ 103
9.05 ꢂ 102
5.40 ꢂ 102
1.79 ꢂ 103
3.09 ꢂ 103
2.82 ꢂ 102
5.07 ꢂ 102
2.31 ꢂ 102
4.20 ꢂ 102
1.62 ꢂ 102
32
35
36
37
38
47
48
49
50
51
61
62
63
64
65
models for porphyrinic macrocycles provides
a qualitative
description of this phenomenon [25e29]. Generally, removal of
magnesium metal or any metal at the centre reduces the symmetry
which leads to splitting of the Q-band giving rise to two distinct
absorbances, Qx and Qy, while the introduction of a metal increases
the symmetry. For compound 32, the Soret band is accompanied by
an absorption peak that is higher in energy, which could be
contributed by phenoxy group.
a
C: Concentration in 2-octanol.
Kow: Octanolewater partition coefficient 1.
b
The metalated Ni(II) and Zn(II) derivatives (40e46 and 52e57)
show two intense
p / p
* absorbances: a low-energy Q band was
present at 596e611 nm, which is accompanied by a slightly higher
energy shoulder, and a high energy B band at 290e350 nm. For
shown in equation (1), which, after manipulation, derived to the
formula shown in equation (4).
metalated porphyrazine derivatives, the symmetry of the
p-chro-
mophore is D4h with the two LUMOs (b2g and b3g) giving rise to
a two-fold degenerate eg level, with the resulting spectra providing
unsplit Q and B absorptions associated with transitions a1u / eg
and a2u / eg as expected in metalated products [30]. However, the
Soret bands are broad, which could arise because of some over-
AðorgÞ ꢂ dðorgÞ
P ¼
(1)
AðaqÞ ꢂ dðaqÞ
where A(org) is the absorbance of the organic layer, A(aq) is the
absorbance of the aqueous layer, d(org) is the dilution factor for the
organic layer, and d(aq) is the dilution factor for the aqueous layer.
The dilution factor is the ratio of the final volume of the sample to
the volume of aliquot according to equations (2) and (3):
lapping
p / p p
* and n / * transitions. When compared to their
precursors, the Soret bands and Q-bands are blue shifted for both
nickel and zinc complexed compounds. The Q-bands demonstrate
similar features in all these porphyrazines, i.e., they are single
intense bands with shoulders at slightly higher energy.
Vf ðorgÞ
dðorgÞ ¼
(2)
VðorgÞ
VfðaqÞ
VðaqÞ
3.5. Partition coefficients
dðaqÞ ¼
(3)
The partition coefficients of the protected and non-protected
compounds were measured between 2-octanol and aqueous
phosphate buffered saline (PBS) and compared to non-carbohy-
drate-substituted pigments. The porphyrazines analysed in the
present study frequently displayed limited solubility in 2-octanol,
although sufficient of each pigment dissolved in order to perform
the experiments (given their high extinction coefficients, only small
amounts are required to solubilise in order to obtain accurate data).
Each porphyrazine was dissolved in 10 mL of 2-octanol by stirring
for 8e12 h. Undissolved material was filtered and PBS solution
(10 mL) was added and the mixture was vigorously stirred for 12 h
after which the two layers were separated and analysed. The
concentration of each solution was accurately determined making
use of extinction coefficients as calculated from results of the
present study (in, for example, DCM), together with UVevisible
absorption data (see Table 1). The analysis of the aqueous layer
required relatively large samples (10 mL) because of the very low
concentrations of most of the porphyrazines studied in the aqueous
layers at the pH value of 7.4. These samples were then dissolved in
a 2.0 M solution of HCl in THF (10 mL). Small amounts (0.5e2.0 mL)
of the organic phase were diluted with appropriate quantities of the
acidic THF solution and the aqueous buffer system to bring the
organic phase samples to conditions identical to those under which
the aqueous phase samples were measured. All electronic spec-
trophotometric measurements were carried out using 1 cm path
length cells. The absorbances as measured were used in subsequent
calculations of the partition coefficients, starting with the formula
where Vf(org) is the final volume of the sample from the organic
layer, V(org) is the volume of the aliquot from the organic layer, Vf
(aq) is the final volume of the sample from the aqueous layer, V(aq)
is the volume of the aliquot of the aqueous layer. Substitution of
equations (2) and (3) into 1 gives equation (4), which is the equa-
tion used to calculate the partition coefficients.
AðorgÞ ꢂ VfðorgÞ ꢂ VðaqÞ
P ¼
(4)
AðaqÞ ꢂ VðorgÞ ꢂ VfðaqÞ
The concentrations of porphyrazines 1, 2, 32, 35e38, 47e51 and
61e65 in 2-octanol and their partition coefficients are listed
according to the carbohydrate and its position of attachment.
However, the first two porphyrazines listed include no carbohy-
drate substituents. Compounds 1 and 2 were used as non-func-
tionalised and functionalised porphyrazine benchmarks,
respectively. The first carbohydrate-substituted porphyrazine is 32
with the carbohydrate residue attached at position 4 and having
a phenoxy group in position 5. The next four porphyrazines have
the carbohydrate located in position 3 (35e38), while the next
three porphyrazines listed have their monosaccharide residues in
position 4 (47e49) and the two porphyrazines with the disaccha-
rides located in position 4 (50 and 51) are shown last.
Porphyrazines 61e65 are deprotected porphyrazines having
their isopropylidene acetal cleaved and they have different carbo-
hydrates at different positions. All compounds tested demonstrated
improved solubility in the aqueous phase over the test compounds.

D.B.G. Williams, G.B. Mbatha / Dyes and Pigments 88 (2011) 65e74
73
The results tabulated in Table 1 and shown in Fig. 1 illustrate a one
Appendix. Supplementary data
to two orders of magnitude decline of the partition coefficients into
2-octanol (corresponding to improved water solubility) with
carbohydrate attachment, when compared to non-carbohydrate-
substituted porphyrazines 1 and 2. The partition coefficients for
porphyrazines 1 and 2 are in the region of 1.01e1.21 ꢂ104 whereas
those of carbohydrate-substituted porphyrazines 35e38 and 47e51
clearly indicate higher water solubility. The results show that there
is no clear or strong trend connecting to either the carbohydrate or
the position of attachment of the carbohydrate onto the benzo ring
to the extraction coefficients, save that all of these compounds
demonstrated improved water solubilities over their unfunction-
alised counterparts.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.dyepig.2010.05.002.
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Acknowledgements
The authors thank the National Research Foundation of South
Africa, Medical Research Council of South Africa and the University
of Johannesburg for funding.
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