Synthesis, properties and drug potential of the photosensitive alkyl- and alkylsiloxy-ligated silicon phthalocyanine Pc 227

Article abstract of DOI:10.1039/c4pp00321g

The photosensitive, alkyl- and alkylsiloxy-ligated silicon phthalocyanine, SiPc[(CH₂)₃SH][OSi(CH₃)₂(CH₂)₃N(CH₃)₂], Pc 227, has been prepared and characterized. This phthalocyanine yields the experimental photodynamic therapy (PDT) drug Pc 4, SiPc[OH][OSi(CH₃)₂(CH₂)₃N(CH₃)₂], when irradiated with red light. To provide an understanding of the process by which Pc 227 and other alkyl-alkylsiloxysilicon phthalocyanines such as Pc 227 are photolyzed, bond dissociation energy, natural bond orbital (NBO) charge distribution, spin density distribution, nucleus-independent chemical shift (NICS), and electron localization function (ELF) calculations have been carried out on two models related to it. These show that the lowest energy pathway for the photolysis of Pc 227 is a homolysis involving a phthalocyanine π radical having a low Si_Pc-C bond dissociation energy. The promise of the results of this study for synthetic chemistry and drug development is discussed. This journal is

Full text of DOI:10.1039/c4pp00321g

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Synthesis, properties and drug potential of the
photosensitive alkyl- and alkylsiloxy-ligated
silicon phthalocyanine Pc 227
Cite this: Photochem. Photobiol. Sci.,
2014, 13, 1690
Jun Li, Yang Yang, Ping Zhang, James R. Sounik and Malcolm E. Kenney*
The photosensitive, alkyl- and alkylsiloxy-ligated silicon phthalocyanine, SiPc[(CH2)3SH][OSi(CH3)2(CH2)3N(CH3)2],
Pc 227, has been prepared and characterized. This phthalocyanine yields the experimental photodynamic
therapy (PDT) drug Pc 4, SiPc[OH][OSi(CH3)2(CH2)3N(CH3)2], when irradiated with red light. To provide an
understanding of the process by which Pc 227 and other alkyl-alkylsiloxysilicon phthalocyanines such as
Pc 227 are photolyzed, bond dissociation energy, natural bond orbital (NBO) charge distribution, spin
density distribution, nucleus-independent chemical shift (NICS), and electron localization function (ELF)
calculations have been carried out on two models related to it. These show that the lowest energy
pathway for the photolysis of Pc 227 is a homolysis involving a phthalocyanine π radical having a low
SiPc–C bond dissociation energy. The promise of the results of this study for synthetic chemistry and drug
development is discussed.
Received 21st August 2014,
Accepted 27th September 2014
DOI: 10.1039/c4pp00321g
www.rsc.org/pps
Introduction
The widespread use of alkylsiloxanes in research and industry
is due in large part to the resistance of normal Si–C bonds to
thermal, chemical and photolytic attack. However, early in the
development of the chemistry of alkyl-alkylsiloxysilicon phthalo-
cyanines it was found that the SiPc–C bond in such phthalo-
cyanines is not stable to white light. After further investigation,
it was found that this bond is photolyzed by light in the
410–480 and 620–670 nm ranges (ranges which overlap partly
and completely the Soret and Q-bands of silicon phthalo-
cyanines), but that it resists photolysis in the 470–530 nm range.
It was further found that it resists attack by concentrated sulfu-
ric acid and methanolic NaOH, and pyrolysis by temperatures
up to about 350°.1 These findings opened a path to the syn-
thesis of a variety of silicon phthalocyanines including the
extensively-studied experimental photodynamic therapy (PDT)
drug SiPc[OH][OSi(CH3)2(CH2)3N(CH3)2], Pc 4, Fig. 1a.2–14 The
photochemical properties of phthalocyanines have made them
promising PDT drugs and prodrugs.15–18
Fig. 1 The structures of (a) SiPc[OH][OSi(CH3)2(CH2)3N(CH3)2], Pc 4,
and (b) SiPc[(CH2)3SH][OSi(CH3)2(CH2)3N(CH3)2], Pc 227.
systems, transportable in them to malignant tissues, and then
photolyzable with red light to Pc 4.19,20 In short, Pc 227 pro-
vides a key building block for a conjugate that has the poten-
tial to be an intravenous prodrug able to deliver Pc 4 to
malignant tissues. Further, it has the potential to be a topical
prodrug which can deliver Pc 4 to such tissues.20
Because the photolysis of the SiPc–C bond in alkyl-alkyl-
siloxysilicon phthalocyanines has both synthetic and potential
practical uses, the mechanism of its photolysis is of interest.
In order to gain more understanding of this, we have carried
out bond dissociation energy, natural bond orbital (NBO)
charge distribution, spin density distribution, nucleus-inde-
pendent chemical shift (NICS), and electron localization func-
tion (ELF) calculations on two model species. These
calculations indicate that the photolysis of the SiPc–C bond in
alkyl-alkylsiloxysilicon phthalocyanines proceeds by a homo-
lytic pathway, and that a transient phthalocyanine π radical in
this pathway is stabilized by delocalization. They also indicate
that this stabilization makes a major contribution to a
reduction in the bond dissociation energy of the SiPc–C bond,
We now have made the new alkyl-alkylsiloxysilicon phthalo-
cyanine SiPc[(CH2)3SH][OSi((CH3)2(CH2)3N(CH3)2], Pc 227,
Fig. 1b. This compound has significant structural similarities
to Pc 4 and forms a conjugate with gold nanoparticles which
gives Pc 4 when irradiated with red light in a nonpolar
medium.19 It has the potential to be dispersible in biological
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106,
USA. E-mail: mek9@case.edu
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and that it is this reduction that allows the photolysis to 817.60. Pc 226 is a green solid. It is soluble in CH2Cl2, di-
proceed with low-energy, red light.
methylformamide, and toluene, and insoluble in hexanes.
[S(CH2)3SiPcOSi(CH3)2(CH2)3N(CH3)2]2, Pc 228. A solution
of Pc 226 (15 mg) in ethanol (3 mL) was treated with an
aqueous solution of NaOH (2.0 N, 20 μL), stirred for 1 h and
evaporated to dryness by rotary evaporation (room tempera-
ture). The solid was chromatographed (basic Al2O3 III, CH2Cl2–
triethylamine solution, 70 : 1), air-dried and weighed (5 mg,
18%). UV-vis (toluene) λmax, nm (log ε): 675 (5.3). NMR
(CDCl3): δ 9.46 (m, 16H, 1, 4-Pc H), 8.23 (m, 16H, 2, 3-Pc H),
1.53 (s, 12H, NCH3), 0.76 (t, 4H, Si(CH3)2(CH2)2CH2), −0.98 (t,
4H, Si(CH2)2CH2), −1.31 (m, 4H, Si(CH3)2CH2CH2), −2.42 (t,
4H, Si(CH3)2CH2), −3.06 (s, l2H, SiCH3), −4.38 (m, 4H,
SiCH2CH2), −6.52 (t, 4H, SiCH2). HRMS-ESI (m/z): l/2[M +
2H]2+ calcd for M as C84H80N18O2S2Si4, 775.2688; found,
775.2696. Pc 228 is a green solid. It is soluble in CH2Cl2,
C2H5OH, dimethylformamide and toluene, and insoluble in
hexanes. Solutions of Pc 228 in CH2Cl2 and toluene are photo-
sensitive, and solutions of it in l,2,3,4-tetrahydronaphthalene
Experimental details
Instrumentation
A Perkin–Elmer IR 598 spectrometer (Perkin Elmer, Shelton,
CT) was used to collect the infrared spectra, a Perkin–Elmer
Lambda 25 Spectrometer and fused silica cells (1.00 cm Fisher
Scientific, Pittsburgh, PA) were used to collect the UV-vis
spectra, and a Varian INOVA 400 MHz spectrometer (Varian,
Palo Alto, CA) was used to collect the NMR spectra. A KRATOS
MS-50 Mass Spectrometer (Ion Tech, Manchester, UK) was
used by the Washington University Center for Biomedical and
Bioorganic Mass Spectrometry Center (St Louis, MO) to obtain
the mass spectra.
Synthesis
SiPc[Cl][(CH2)3Cl], Pc 309. A mixture of 1,3-diiminoiso- are thermally unstable above ∼170 °C.
indoline (1.0 g), Cl(CH2)3SiCl3 (0.92 mL), and 2,6-lutidine
SiPc[(CH2)3SH][OSi(CH3)2(CH2)3N(CH3)2], Pc 227. Under Ar,
(7 mL) was refluxed for 6 h, concentrated to a slurry by rotary a cooled (0 °C) Ar-purged solution of Pc 226 (80 mg) and
evaporation (40 °C), diluted with H2O (∼50 mL) and filtered. ethanol (50 mL) was treated with a cooled (∼0 °C) aqueous
The solid was washed (H2O) and vacuum dried (80 °C).
NaOH solution (1.6 mL, 2.0 N), cooled (0 °C) for 75 min, treated
SiPc[(CH2)3Cl][OSi(CH3)2(CH2)3N(CH3)], Pc 220. A mixture with an aqueous NH4Cl solution (saturated, 40 mL) and
of the crude Pc 309 made in the previous step, CH3OSi- extracted with CH2Cl2 (3 times, ∼20 mL each time). The extract
(CH3)2(CH2)3N(CH3)2 (0.16 g) and chlorobenzene (30 mL) was was evaporated to dryness by rotary evaporation (room tempera-
refluxed for 3 h, and evaporated to dryness by rotary evapor- ture), and the solid was reduced with tri-(n-butyl)phosphine
ation (40 °C). The solid was chromatographed (basic Al2O3 III, (0.025 mL) and CHCl3 (10 mL) under Ar for 30 min, and evapor-
CH2Cl2–N(CH2CH3)3 solution, 150 : 1), vacuum dried (room ated to dryness by rotary evaporation (room temperature). The
temperature), and weighed (65 mg, 5% based on 1,3-diimino- solid was chromatographed (basic Al2O3 V, CH2Cl2–ethyl acetate
isoindoline). UV-vis (toluene) λmax, nm (log ε): 678 (5.3). NMR solution, 10 : 1), vacuum dried (room temperature), and weighed
(CDCl3): δ 9.63 (m, 8H, 1,4-Pc H), 8.35 (m, 8H, 2,3-Pc H), (61 mg, 80%). UV-vis (toluene) λmax, nm (log ε): 678 (5.5). NMR
1.56 (s, 6H, NCH3), 0.85 (t, 2H, Si(CH2)2CH2), 0.78 (t, 2H, (CDCl3): δ 9.64 (m, 8H, 1,4-Pc H), 8.34 (m, 8H, 2,3-Pc H), 1.55
Si(CH3)2(CH2)2CH2), −1.22 (m, 2H, Si(CH3)2CH2CH2), −2.37 (s, 6H, NCH3), 0.78 (t, 2H, Si(CH3)2(CH2)2CH2), −0.14 (q, 2H, Si
(t, 2H, Si(CH3)2CH2), −2.99 (s, 6H, SiCH3), −3.51 (m, 2H, (CH2)2CH2), −0.43 (t, 1H, SH), −1.21 (m, 2H, Si(CH3)2CH2CH2),
SiCH2CH2), −6.16 (t, 2H, SiCH2). LRMS-ESI (m/z): [M]+ calcd −2.37 (t, 2H, Si(CH3)2CH2), −2.99 (s, 6H, SiCH3), −3.67 (m, 2H,
for C42H40ClN9OSi2, 777.26; found, 777.73. Pc 220 is a green SiCH2CH2), −6.14 (t, 2H, SiCH2). HRMS-ESI (m/z): [M + H]+
solid. It is soluble in CH2Cl2, dimethylformamide, and calcd for M as C42H41N9OSSi2, 776.2772; found, 776.2771. Pc
toluene, and insoluble in hexanes.
227 is a green solid. It is soluble in CH2Cl2, dimethylformamide,
SiPc[(CH2)3S(O)(CH3)][OSi(CH3)2(CH2)3N(CH3)2], Pc 226. A and toluene, and insoluble in hexanes.
mixture of Pc 220 (100 mg), potassium thioacetate (324 mg),
SiPc[OSi(CH3)2(CH2)3N(CH3)2]2, Pc 12. A mixture of CH3OSi-
and dimethylformamide (16 mL) was warmed (50 °C) for 6 h (CH3)2(CH2)3N(CH3)2 (711 mg) and a suspension of SiPc(OH)2
and evaporated to dryness by rotary evaporation (40 °C). The (284 mg) and pyridine (170 mL) that had been dried by distilla-
solid was treated with H2O (∼50 mL) and extracted with tion (∼10 mL of distillate) was slowly distilled for 4 h (∼10 mL
CH2Cl2 (3 times, ∼30 mL each time). The extract was evapor- of distillate). The reaction solution was evaporated to dryness
ated to dryness by rotary evaporation (40 °C) and the solid was by rotary evaporation (40 °C), and the solid was washed with
chromatographed (basic Al2O3 III, CH2Cl2–ethyl acetate solu- CH3CN, vacuum dried (40 °C) and weighed (356 mg, 83%). UV-
tion, 5 : 1), vacuum dried (room temperature), and weighed vis (dimethylformamide) λmax, nm (log ε): 668 (5.3). NMR
(49 mg, 46%). UV-vis (toluene) λmax, nm (log ε): 678 (5.4). NMR (CDCl3): δ 9.63 (m, 8H, 1,4-Pc H), 8.34 (m, 8H, 2,3-Pc H), 1.65
(CDCl3): δ 9.64 (m, 8H, 1,4-Pc H), 8.31 (m, 8H, 2,3-Pc H), (s, 12H, NCH3), 0.90 (m, 4H, Si(CH3)2(CH2)2CH2), −1.10 (m,
1.55 (s, 6H, NCH3), 1.52 (s, 3H, CH2SC(O)CH3), 0.79 (t, 2H, 4H, Si(CH3)2CH2CH2), −2.26 (m, 4H, Si(CH3)2CH2), −2.87 (s,
Si(CH3)2(CH2)2CH2), 0.29 (t, 2H, Si(CH2)2CH2), −1.23 (m, 2H, 12H, SiCH3). The compound is a blue solid. It is soluble in
Si(CH3)2CH2CH2), −2.38 (t, 2H, Si(CH3)2CH2), −2.99 (s, 6H, CH2Cl2, dimethylformamide, toluene, and insoluble in hexanes.
SiCH3), −3.72 (m, 2H, SiCH2CH2), −6.13 (t, 2H, SiCH2).
SiPc[OH][OSi(CH3)2(CH2)3N(CH3)2], Pc 4. A solution of
LRMS-ESI (m/z): [M]+ calcd for C44H43N9O2SSi2, 817.28; found, unchromatographed Pc 12 (640 mg), trichloroacetic acid
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(672 mg) and CH2Cl2 (90 mL) was stirred at room temperature (185 °C) for 60 min, refluxed for 75 min, and filtered. The
for 5 h. The product was mixed with pyridine (90 mL) and solid was washed (CH3OH, pyridine, CH3OH), vacuum dried
then H2O (90 mL) and the mixture was separated. The aqueous 80 °C and weighed (1.56 g, 69%). IR (Nujol, cm−1): 1377 (s),
layer was washed with CH2Cl2, the washings were filtered, and 1370 (s), 1343 (s), 1255 (w, Si–CH3), 1081 (s), 1014 (w), 886 (m),
the residue was washed with CH2Cl2. The organic layer was fil- 756 (s), 723 (m), 468 (m, Si–Cl). The product is green-brown. It
tered and the filtrate and CH2Cl2 washings were combined is insoluble in common organic solvents.
and evaporated to dryness by rotary evaporation (40 °C). The
SiNc(CH3)(OH), Nc 2. A mixture of Nc 1 (529 mg) and con-
solid was vacuum dried (40 °C) and weighed (638 mg). A solu- centrated H2SO4 (10 mL) was stirred for 2.6 h, poured onto ice
tion of this product (630 mg) and CH2Cl2 was chromato- (70 g) and filtered. The solid was washed (H2O, 3 N NH4OH),
graphed (Al2O3 V, CH2Cl2–ethyl acetate solution, 5 : 1) and the air dried and combined with a solution of 3 N NH4OH and pyr-
eluate was evaporated to dryness by rotary evaporation (40 °C). idine (3 : 35). The suspension formed was refluxed for 1 h and
The solid was washed with CH3CN, vacuum dried (40 °C), and filtered. The solid was washed (pyridine, CH3OH), vacuum
weighed (392 mg, 61% based on SiPc(OH)2 used). UV-vis dried (∼80 °C) and weighed (479 mg, 93%). IR (mineral oil,
(CH2Cl2) λmax, nm (log ε): 669 (5.3). NMR (CDCl3): δ 9.11 (m, cm−1): 3440 (w br, O–H), 1377 (s), 1370 (s), 1349 (m), 1341 (m),
8H, 1,4-Pc H), 8.18 (m, 8H, 2,3-Pc H), 1.35 (s, 6H, NCH3), 0.60 1253 (w, Si–CH3), 1089 (s), 1079 (s), 1042 (s), 884 (m), 802 (m,
(m, 2H, Si(CH3)2(CH2)2CH2), −1.36 (m, 2H, Si(CH3)2CH2CH2), Si–OH), 757 (m), 721 (m). The product is dark green. It is in-
−2.49 (m, 2H, Si(CH3)2CH2), −3.10 (s, 6H, SiCH3). HRMS-FAB soluble in common organic solvents.
(m/z): [M + H]+ calcd for M as C39H35N9O2Si2, 717.2452; found,
SiNc[CH3][OSi((CH2)5CH3)3], Nc 3. A mixture of Nc 2
717.2422. The compound is a blue solid. It is soluble in (389 mg), tri-n-hexylchlorosilane (2.0 mL), tri-n-butylamine
CH2Cl2, dimethylformamide, toluene, and insoluble in hexanes. (2.0 mL) and dry pyridine (30 mL) was refluxed for 2.6 h, fil-
SiPc[OCH3][OSi(CH3)2(CH2)3N(CH3)2], Pc 233. A mixture of tered while hot, vacuum concentrated (∼60 °C), diluted with
Pc 4 (60 mg), CH3OH (900 mg), and pyridine (30 mL) was CH3OH (30 mL) and filtered. The solid was washed (CH3OH,
refluxed for 30 min and concentrated by rotary evaporation pentane), vacuum dried (∼80 °C) and weighed (404 mg, 76%).
(room temperature). The solid was chromatographed (neutral Some of the solid (171 mg) was recrystallized (toluene),
Al2O3 III, CH2Cl2–ethyl acetate solution, 2 : 1), evaporated to washed (CH3OH), vacuum dried (∼90 °C), and weighed
dryness by rotary evaporation (room temperature), vacuum (118 mg, 69%). Mp (°C) 239; IR (Nujol, cm−1) 1376 (s), 1370 (s),
dried (room temperature), and weighed (49 mg, 80%). UV-vis 1349 (s), 1341 (s), 1254 (w, Si–CH3), 1082 (s), 1041 (m), 1026
(toluene) λmax, nm, (log ε): 671 (5.4). NMR(CDCl3): δ 9.63 (m, (m, Si–O–Si), 1016 (m), 802 (m, Si–OH), 761 (s), 721 (m); NMR
8H, 1,4-Pc H), 8.33 (m, 8H, 2,3-Pc H), 1.63 (s, 6H, NCH3), 0.88 (C6D6): δ 10.19 (s, 5,36-NcH), 8.34 (m, 1,4-NcH), 7.59 (m, 2,3-
(t, 2H, γ-CH2), −1.10 (m, 2H, β-CH2), −1.82 (s, 3H, OCH3), NcH), 0.73 (m, ε-CH2), 0.48 (t, t-CH2), 0.40 (m, γ, δ-CH2), −0.65
−2.27 (t, 2H, α-CH2), −2.87 (s, 6H, SiCH3). HRMS-FAB (m/z): (m, β-CH2), −1.76 (m, α-CH2), −4.89 (s, SiNc–CH3). Anal Calcd
[M + H]+ calcd for C40H37N9O2Si2, 732.2687: found 732.2690. for C67H66N8Si2O: C, 76.24; H 6.30; Si, 5.32. Found: C, 76.26;
Pc 233 is a purple solid. It is soluble in CH2Cl2, dimethylform- H, 6.26; Si, 5.40. The compound is bright blue-green. It is
amide and toluene and insoluble in hexanes.
soluble in toluene, benzene, and CHCl3, and insoluble in
SiPc(CH3)Cl, Pc 310. A mixture of 1,3-diiminoisoindoline CH3OH and hexanes.
(2.02 g, 13.9 mmol), methyltrichlorosilane (1.15 mL,
SiNc[OH][OSi((CH2)5CH3)3], Nc 4. A cooled (0 °C) mixture of
9.79 mmol) and quinoline (19 mL) was refluxed for 90 min, fil- Nc 3 (593 mg) and toluene (750 mL) was stirred in direct sun-
tered while hot, washed (acetone, ether, toluene). The filtrate light for 1.5 h. The solution was filtered and the filtrate was
was cooled, refiltered and the solid was washed. The two evaporated to dryness by rotary evaporation (∼60 °C), vacuum
solids were combined and weighed (1.50 g, 73% based on di- dried (∼90 °C) and weighed (84 mg, 40%). Some of the solid
iminoisoindoline). Pc 310 is a purple solid. It is insoluble in (209 mg) was recrystallized (toluene), vacuum dried (∼90 °C)
CH2Cl2, dimethylformamide, toluene and hexanes.
and weighed (84 mg, 40%). Mp (°C) ∼370; IR (Nujol) 3440
SiPc[CH3][(OSi(CH2CH3)3)], Pc 311. A mixture of Pc 310 (w br, O–H), 1378 (s), 1366 (s), 1353 (s), 1342 (m), 1096 (s),
(222 mg, 0.376 mmol), triethylsilanol (0.228 mL, 1.49 mmol), 1079 (s), 1041 (m), 1036 (m, Si–O–Si), 1015 (m), 760 (m),
chlorobenzene (68 mL) and pyridine (10 mL) was refluxed for 723 (m). NMR (C6D5CD3, 91 °C): δ 9.22 (s, 5,36-NcH), 8.17 (m,
20 min, filtered and evaporated to dryness by rotary evapor- 1,4-NcH), 7.74 (m, 2,3-NcH), 0.43 (m, ε-CH2), 0.24 (t, t-CH2),
ation (40 °C). The solid was chromatographed (basic alumina 0.00 (m, γ, δ-CH2), −0.95 (m, β-CH2), −2.01 (m, α-CH2); Anal
III, CH2Cl2–hexanes, 1 : 1), washed (acetonitrile), vacuum dried Calcd for C66H64N8SiO2: C, 74.97; H, 6.10; Si, 5.31. Found:
(60 °C), and weighed (157 mg, 61%). UV-vis (toluene) λmax, nm C, 74.54; H, 5.88; Si, 5.63. The compound is blue-green. It
(log ε): 675 (5.4). NMR (CDCl3): δ 9.63 (m, 1,4-Pc H), 8.32 (m, is slightly soluble in toluene and CHCl3, and insoluble in
2,3-Pc H), −1.28 (t, CH2CH3), −2.51 (q, CH2CH3), −6.40 (s, CH3OH.
SiCH3). Pc 311 is a purple solid. It is soluble in CH2Cl2, di-
methylformamide and toluene, and insoluble in hexanes.
Computations
SiNc(CH3)Cl, Nc 1 (Nc represents a naphthalocyanine macro- The geometry optimization of the model species used in the
cycle). A mixture of SiCH3Cl3 (1.2 mL), 1,3-diiminobenz( f )iso- computations was carried out with the Gaussian 09 package.21
quinoline (2.24 g) and dry quinolone (35 mL) was heated All optimized stationary points were confirmed to be energy
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minima on the corresponding potential energy surfaces
The synthesis used for Pc 4 via Pc 12, Scheme 2, has been
through vibrational frequency analyses (i.e., by verifying the described earlier in the patent literature.22 The similarity of the
lack of imaginary frequencies). The spin-restricted method was synthesis of the pair of compounds SiPc(CH3)[OSi(CH2CH3)3],
used for the singlet states and the spin-unrestricted method Pc 311, and SiNc(CH3)[OSi(CH2)5CH3)3], Nc 3, Schemes 3 and 4,
was used for the doublet states, i.e., the open-shell systems.
illustrates again the close (but not identical) relationship
between corresponding pairs of silicon phthalocyanines and
naphthalocyanines.
Results and discussion
NMR spectra
Syntheses
As expected, the NMR spectra of Pc 227 and Pc 233 in CDCl3
show large ring-current effects, Fig. 2. The resonance at
∼6 ppm in the spectrum of Pc 227 and its absence in that of
Pc 233 provides unambiguous evidence for the presence of an
SiPc–C bond in Pc 227.
The Pc 309 synthesized, Scheme 1, was very impure. This pro-
hibited giving a meaningful yield of it. No way was found to
improve its yield. The low yield of Pc 309 was the primary
cause of the low overall yield of Pc 227.
The fourth step in the synthesis of Pc 227, the NaOH-thio-
acetate hydrolysis step, produced a reaction mixture contain-
ing both Pc 227 and its disulfide oxidation dimer, Pc 228, even
Bond dissociation energy of the Si–C bond in SiPc(OH)(CH3),
Model 1
when care was taken to exclude air. This led to the use of tribu- The bond dissociation energy (BDE) of the SiPc–C bond in SiPc-
tylphosphine in the last step.
(OH)(CH3), Model 1, was determined using the B3LYP and
Scheme 1 The synthesis of Pc 220, Pc 226 and Pc 227.
Scheme 2 The synthesis of Pc 12, Pc 4 and Pc 233.
Scheme 3 The synthesis of Pc 310 and Pc 311.
Scheme 4 The synthesis of Nc 1, Nc 2, Nc 3 and Nc 4.
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Fig. 2 The NMR spectra of Pc 227 and Pc 233.
Table 1 The BDEs of the SiPc–C and SiPc–O Bonds in Model 1, SiPc
BP86 density functionals at the DFT/6-31G(d) level. BP86 is a
generalized gradient approximation (GGA) method23,24 and
B3LYP is a hybrid GGA with 20% exact exchange.25,26 Values
for both heterolytic cleavage of the bond to SiPc+ and L− and
homolytic cleavage of it to SiPc•, and L• were determined,
Table 1. As is seen, the values given by the two functionals are
quite similar.
(OH)(CH3) (kcal mol−1
)
a
c
Bond
Cleavage
E1
ZPEb
E2
B3LYP
BP86
SiPc–C
iPc–O
Hetero
Homo
Hetero
Homo
187
42
196
79
−5
−5
−3
−4
182
37
193
75
S
The BDEs for heterolytic cleavage of the SiPc–C bond are
high as expected, but those for its homolytic cleavage are
∼50 kcal mol−1 lower than those that are typical for this bond,
SiPc–C
SiPc–O
Hetero
Homo
Hetero
Homo
190
45
199
84
−5
−5
−3
−4
185
40
196
79
∼90 kcal mol−1 27
This is attributed to delocalization of the
.
unpaired electron of the phthalocyanine π radical generated by
the homolysis of the bond and the consequent stability of it.
a E1, electronic energy. b ZPE, zero-point correction. c E2, sum of E1 and
ZPE.
NBO charges of Models 1 and 2
6-31G(d) level. Only the B3YLP functional was used in this work
A NBO analysis of the charge distribution of Model 1, SiPc- since both it and the BP86 functional gave similar BDE values.
(OH)(CH3), and Model 2, SiPc(OH)•, was carried out with NBO
The NBO data show that the negative charge on the
version 3 28 implemented in Gaussian 09 with at the B3LYP/ phthalocyanine ring is considerably larger in the case of
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ELF domains in Model 2
Table 2 The NBO Charges in Model 1, SiPc(OH)(CH3), and Model 2,
SiPc(OH)•
Spatial grids of the electron localization function (ELF)
domains of Model 2 were generated with Checkden35 and a
topological analysis of its ELF basins was conducted with
Topmod36 both with a wave function generated at the B3LYP/
6-31G(d) level, Fig. 3c (ELF is a function which gives a quantitat-
ive Lewis description of a molecule). The results reveal the ELF
domains expected for the bonding and lone-pair electrons. No
nonbonding localization domain is shown near the central
silicon as would be expected if the unpaired electron were loca-
lized on it. Topological analysis of the ELF data shows a divi-
sion of the molecular space into 117 basins with 42 being
core, 5 monosynaptic and 70 disynaptic. These basins corres-
pond to 42 non-hydrogen atom cores and 5 lone pairs (4 aza-
nitrogen pairs and 1 oxygen pair), and 70 bonds (32 C–C
bonds, 16 C–H bonds 16 C–N bonds, 4 Si–C bonds, 1 O–H
bond and 1 Si–O bond). No ELF attractor corresponding to a
localized unpaired electron near the silicon is evident. This is
consonant with the delocalization of the unpaired electron
over the macrocycle.33,34
Si
Me
Pc
OH
Model 1
Model 2
2.20
2.32
−0.49
0.00
−1.09
−1.73
−0.62
−0.60
Model 2 than Model 1, Table 2 and Fig. 3. This result is con-
sistent with the presence of a delocalized electron in the ring
of Model 2. Support for the postulated presence of a deloca-
lized electron in the SiPc• π radical is found in an earlier EPR
study of the photolysis of silicon porphyrins in which a species
was found which under Ar retained 95% of its signal intensity
after 1 day and 86% after 50 days.29
Spin densities of Model 2
The spin densities for Model 2 are given in Fig. 3a. The results
indicate that the unpaired electron of this model is delocalized
largely over its inner 16-membered ring.
NICS shifts in Models 1 and 2
Si–O bond dissociation energies for Model 1
Nucleus-independent chemical shifts (NICS)30,31 of Model 1
SiPc(OH)(CH3), and Model 2, SiPc(OH)•, were determined with
the gauge independent atomic orbital (GIAO) method32 at the
B3LYP/6-311+G(2d,p) level with geometries optimized at the
B3LYP/6-31G(d) level. The negative sign of all the NICS values
in Model 1 are consistent with the ring-current effects
observed in the NMR spectra of Pc 227 and Pc 309, Fig. 2. The
negative sign of the values for the benzo rings and the positive
sign of the values for the inner, nonbenzo rings of Model 2
indicate that its benzo rings are aromatic and its nonbenzo
rings are antiaromatic. This is consistent with the conclusion
that the number of electrons in the macrocycle of Model 2 is
odd.33,34
Calculated SiPc–O BDEs of Model 1 were determined in the
same way as those for its SiPc–C BDEs, Table 1. The calculated
BDEs for the heterolytic cleavage of the SiPc–O bond are high.
Those for the homolytic cleavage of it are about ∼50 kcal
mol−1 lower than those typical for the homolytic cleavage of
such bonds, ∼125 kcal mol−1 27
While substantial, this
.
reduction is not enough to lead to homolytic cleavage of the
SiPc–O bond by red light or by ambient temperatures, and it is
this that allows the selective cleavage of the SiPc–C bond by red
light in the presence of the SiPc–O bond.
Irradiation of Nc 3 with red light
The fact that the NICS values for the inner nonbenzo rings The irradiation of a toluene solution of SiNc(CH3)[OSi(C6H13)3],
of Model 2 become more positive relative to those of the benzo Nc 3, over a period of two days with sunlight from which
rings (when compared to Model 1), can be rationalized by wavelengths shorter than 660 nm had been filtered did not
noting that the spin density distribution results indicate that alter its NMR spectrum. This shows that the SiNc–C bond, in
the unpaired electron is delocalized largely over the inner contrast with the SiPc–C bond, resists photolysis by red light.
rings.
This is as expected since the Q-band of silicon naphthalocyanines
Fig. 3 The (a) spin density distribution in Model 2 (isovalue = 0.004), (b) NICS shifts in Model 1 (blue) and Model 2 (red), and (c) ELF domains in
Model 2, ( f = 0.84).
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Fig. 4 Selective cleavage of the SiPc–C bond and formation of the SiPc–O bond in the presence of nucleophiles.
is at ∼775 nm,37 and light of this wavelength probably cannot topical release of silicon phthalocyanine drugs from prodrug
provide enough energy to homolytically cleave the SiNc–C nonconjugated alkyl-alkylsiloxysilicon phthalocyanines.20
bond. (The irradiation of a toluene solution of Nc 3 with
unfiltered sunlight gave Nc 4, Scheme 4. The photolytic sensi-
tivity of Nc 3 under these conditions is attributable to absorp-
tion of more energetic light by its Soret band.)
Summary and conclusions
The compounds SiPc[(CH2)3SH][OSi(CH3)2(CH2)3N(CH3)2], Pc
227, and SiNc[CH3][OSi((CH2)5CH3)3], Nc 3, have been pre-
pared, purified and characterized. The SiPc–C bond in Pc 227
is photolyzed by red light when the compound is in solution,
while the SiNc–C bond of Nc 3 is not. Calculations on the
model compound SiPc(CH3)(OH), Model 1, and π radical
SiPcOH•, Model 2, show that the homolytic bond dissociation
energy of the SiPc–C bond of Model 1 is reduced from the
value typical for an ordinary Si–C bond by about 50 kcal
mol−1. This reduction is due in large part to a delocalization of
the unpaired electron of an intermediate silicon phthalo-
cyanine π radical, SiPc[OSi(CH3)2(CH2)3N(CH3)2]•, in the reac-
tion pathway. While the lowering of the bond energy of the
SiPc–C bond leads to its photochemical instability it is insuffi-
cient to cause to its thermal instability at ambient tempera-
tures. The lowered bond energy of the SiPc–C bond makes a
variety of photochemically labile but chemically and thermally
stable synthetic intermediates accessible. It also makes poss-
ible intravenous silicon phthalocyanine-nanoparticle conjugate
prodrugs that can be activated by low-energy visible light. This
light does not cause the deleterious side effects that blue light
or ultraviolet light can. The lowered bond energy also makes
possible topical nonconjugated silicon phthalocyanine pro-
drugs that can be activated by red light. The SiNc–C bond of Nc
3 is not photolyzed by red light because the Q-band of silicon
naphthalocyanines is shifted by about 100 nm to the red rela-
tive to the band of phthalocyanines, and the energy of the
light absorbed by this band is insufficient to cause homolytic
cleavage of the SiNc–C bond.
Essential elements in the selective photolysis of
alkylsiloxysilicon phthalocyanines by red light
The essential elements making possible the selective photo-
lysis of the SiPc–C bond of alkyl-alkylsiloxysilicon phthalo-
cyanines such as Pc 227 by red light are: (1) a Q-band absorption
near 670 nm, (2) an SiPc–C bond which is weak as a result of
the Si being embedded in the macrocycle, and (3) an SiPc–O
bond which is still relatively strong (although its Si is thus
embedded). These elements probably can also be found in
alkylsilicon phthalocyanines with trans alkoxy or aryloxy
ligands instead of siloxy ligands, i.e., RSiPcOR or RSiPcOAr.
However, they cannot be expected in alkyl-alkylsiloxysilicon
tetrapyrroles as a whole because most do not have strong red
absorptions.
Applications of the photolytic sensitivity of the SiPc–C bond to
red light
The selective cleavage of the SiPc–C bond has already proven
useful for the preparation of Pc 4 from Pc 3, SiPc[CH3]-
[OSi(CH2)3N(CH3)2],3 of Pc 233 (the methoxy analogue of Pc 4 19
)
from Pc 227 and of other silicon phthalocyanines.38,39 These
results make it apparent that a variety of target compounds
can be prepared by treating Pc 227 and other alkyl-alkylsiloxy-
silicon phthalocyanines with red light in the presence of
nucleophiles, Fig. 4. This approach probably can be further
extended to some ring-substituted alkyl-alkylsiloxysilicon
phthalocyanines, and thus offers considerable flexibility.
A possible use of the selective photolytic cleavage of the
SiPc–C bond is the intravenous release in biological systems of
silicon phthalocyanine drugs from prodrug silicon phthalo-
cyanine-nanoparticle conjugates by irradiation with red
Acknowledgements
light.19,20 Since this approach does not use blue or ultraviolet Professor Clemens Burda and Dr. Tennyson L. Doane are
light, it is suited to systems in which hemoglobin is present. thanked for helpful conversations. This work was supported by
Precedent for the use of prodrugs which can be photocleaved in part by allocations of computing resources from the Case
is found in the work of Rotello et al.40–42 Another possible use High Performance Computing System and the Ohio Super-
of the selective photolytic cleavage of the SiPc–C bond is the computer Center.
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13 M. E. Rodriguez, J. Kim, G. B. D. Santos, K. Azizuddin,
J. Berlin, V. E. Anderson, M. E. Kenney and N. L. Oleinick,
Binding to and Photo-Oxidation of Cardiolipin by the
Phthalocyanine Photosensitizer Pc 4, J. Biomed. Opt., 2010,
15, 051604.
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