Octacationic and Axially Di-substituted Silicon

(IV) Phthalocyanines for Photodynamic

Inactivation of Bacteria.

Eveline van de Winckel,a Bruna David,b Marta Moreno Simoni,a Jos A. Gonzlez-

Delgadoc,d*, Andrs de la Escosura,a,e* ngela Cunha,b* and Toms Torresa,e,f*

E-mail addresses: jose.gonzalez@dqcm.uhu.es (Jos A. Gonzlez-Delgado) phone (+34)

959219999; fax: (+34) 959219983, andres.delaescosura@uam.es (Andrs de la Escosura) phone
(+34) 914972773; fax: (+34) 914973966, acunha@ua.pt (ngela Cunha) Tel: (+35) 1234
370784 tomas.torres@uam.es (Toms Torres) phone (+34) 914974151; fax: (+34) 914973966
 1. Synthesis

N N N N

O O O O
O Cl O
O OH O
N N N N
N N N NaOMe N N N
N N Si N N N Si N
N N H2O/EtOH N N
N N reflux, 5h N N
O O
Cl O 80% OH O
O O O O
4 5
N N
N N

-
RSi Cl pyridine
reflux, 18h
N N

O O
O OR
N O
N
N N N
N N Si N
N N
1 R=H a R= Si b R= Si N N
O
OR O
O O
-
6ac
N
N

c R= Si
DMF
CH3I rt or 40 C, 2h
N N

O O
O
OR O
N N
N N N
N N Si N
N N
N N
O
OR O
O O

N 1
-
2ac N

Scheme S1. Synthetic route for the preparation of the target SiPcs 1 and 2a-c

The synthesis of bis(pyridin-3-yloxy)-dihydroxyl SiPc (5) was accomplished according

to the procedures described in ref. [1].

1.1.1. Bis(triisobutylsilyl) SiPc (6a):

SiPc 5 (0.050 g, 0.038 mmol) was dissolved in 3 mL of dry pyridine at 115 C

under an argon atmosphere. Triisobutylchlorosilane (0.254 mL, 0.947 mmol) was added

dropwise to the reaction mixture via syringe. After 8 h, another portion of

triisobutylchlorosilane (0.183 mL, 0.682 mmol) was added. The reaction mixture was

refluxed for another 9 h, after which the solvent was evaporated to dryness. The remaining

solid was washed extensively with chloroform and the filtrate was collected and

evaporated to dryness and subjected to a trituration in heptane, in which the solid was

collected and washed with heptane and water to obtain the pure compound 6a (0.025 mg,

38%) as a dark green solid. 1H NMR (300 MHz, CDCl 3 , ppm): 9.38 (s, 8H, H3), 8.66

(d, J = 2.7 Hz, 8H, H2), 8.58 (d, J = 4.6 Hz, 8H, H3), 7.84 (dd, J = 4.9, 1.8 Hz, 8H,

H5), 7.68-7.63 (m, 8H, H4), 0.44 (d, 36H, J = 6.5Hz, H3), -0.85 (m, 6H, H2), -2.44

(d, 12H, J = 7 Hz, H1). 13C NMR (75 MHz, CDCl 3 , ppm): 154.3, 150.8, 148.6, 145.8,

141.1, 133.6, 125.7, 125.1, 116.0, 31.4, 25.8, 25.3, 22.9. MS (MALDI-TOF, DCTB): m/z

= 3374.4 [2M-iBu]+ (10), 1715.6 [M]+ (30), 1499.4 [M-L ax ]+ (100). HR-MS (MALDI-

TOF, DCTB): m/z calcd for C 96 H 94 N 16 O 10 Si 3 [M]+, 1715. 6667; found: 1715.6561. UV-

VIS (DMF): max (nm) (log ): 676 (5.29), 646 (4.40), 609 (4.46), 361 (4.85). FT-IR (neat)

(cm-1): 2950, 1574, 1458, 1418, 1282, 1214, 1087, 1019. Mp: > 250 C.

1
H-NMR (500 MHz, 298K, CDCl 3 ) of 6a
 13
C-NMR (125 MHz, 298K, CDCl3) of 6a

MALDI-TOF and HR-MS-MALDI spectrum (inset) of 6a

1.1.2. Bis(n-butylsilyl) SiPc (6b):

SiPc 5 (0.050 g, 0.038 mmol) was dissolved in 10 mL of dry pyridine at 115 C under an

argon atmosphere. n-Butylchlorosilane (0.252 mL, 0.947 mmol) was added dropwise to

the reaction solution via syringe. After 8 h, another portion of n-butylchlorosilane (0.181

mL, 0.682 mmol) was added. Purified as described above for SiPc 6a, yielding 6b (0.021

mg, 32%) as a dark green solid. 1H NMR (300 MHz, CDCl 3 , ppm): 9.19 (s, 8H, H3),

8.64 (d, J = 2.7 Hz, 8H, H2), 8.54 (dd, J = 3.5, 1.0 Hz, 8H, H3), 7.61 (m, 8H, H5),

7.48-7.44 (m, 8H, H4), 0.13-0.22 (m, 30H, H3-4), -1.19 (m, 12H, H2), -2.38 (m,

12H, H1). C NMR (75 MHz, CDCl 3 , ppm): 153.9, 150.3, 147.9, 144.9, 140.26,
13

133.1, 125.9, 124.9, 115.7, 31.3, 29.9, 25.7, 23.2. MS (MALDI-TOF, DCTB): m/z =

3374.4 [2M iBu]+ (1), 1715.6 [M]+ (100), 1500.4 [M L ax +H]+ (40), 375.3 (30). HR-

MS (MALDI-TOF, DCTB): m/z calcd. for C 96 H 94 N 16 O 10 Si 3 [M]+, 1715.6667; found,

1715.6584. UV-VIS (DMF): max (nm) (log ): 675 (5.11), 645 (4.28), 608 (4.32), 361
(4.74). FT-IR (neat) (cm-1): 2953, 2919, 2868, 1575, 1459, 1418, 1284, 1214, 1086,

1036, 899, 703. Mp: > 250 C

1
H-NMR (500 MHz, 298K, CDCl 3 ) of 6b

13
C-NMR (125 MHz, 298K, CDCl3) of 6b
 MALDI-TOF and HR-MS-MALDI spectrum (inset) of 6b

1.1.3. Bis(triphenylsilyl) SiPc (6c):

SiPc 5 (0.050 g, 0.038 mmol) was dissolved in 10 mL of dry pyridine at 115 C

under an argon atmosphere. Triphenylchlorosilane (0.279 g, 0.947 mmol) was added

dropwise to the reaction solution via syringe. After 8 h, another portion of

triphenylchlorosilane (0.201 g, 0.682 mmol) was added. Purified as described above for

SiPc 6a, yielding 6c (0.024 mg, 34%) as a dark green solid. 1H NMR (300 MHz, CDCl 3 ,

ppm): 9.04 (s, 8H, H3), 8.68 (s, 8H, H2), 8.58 (d, J = 2.6 Hz, 8H, H3), 7.65 (dd, J =

5.9 ,2.2 Hz, 8H, H5), 7.53 (m, 8H, H4), 6.85 (t, J = 7.4 Hz, 6H, H4) , 6.48 (t, J = 7.4

Hz, 12H, H3), 4.87 (d, J = 7.0 Hz, 12H, H2). 13C NMR (75 MHz, CDCl 3 , ppm):

154.0, 149.9, 148.0, 144.7, 139.8, 133.8, 132.9, 132.8, 128.4, 126.5, 126.0, 125.0, 115.7,

31.1. MS (MALDI-TOF, DCTB): m/z = 1835.3 [M]+ (100), 1758.3 [M C 5 H 6 ]+ (2)

1560.3 [M L ax ]+ (10). HR-MS (MALDI-TOF, DCTB): m/z calcd. for

C 108 H 70 N 16 O 10 Si 3 [M]+, 1835.4790; found: 1835.4770. UV-VIS (DMF): max (nm) (log
): 681 (5.10), 649 (4.27), 613 (4.35), 363 (4.26). FT-IR (neat) (cm-1): 3067, 1460, 1428,

1118, 738, 711. Mp: > 250 C.

1
H-NMR (500 MHz, 298K, CDCl 3 ) of 6c

13
C-NMR (125 MHz, 298K, CDCl 3 ) of 6c
 MALDI-TOF and HR-MS-MALDI spectrum (inset) of 6c

1.1.4. General procedure of methylation of silicon (IV) phthalocyanines (1 and 2a-d)

SiPc (5 or 6a-c) (0.014 mmol) was dissolved in dry DMF (2 mL) under Ar atmosphere

and CH 3 I (0,5 mL) was added. The mixture was stirred at rt (for 6a-b) or at 50 C (for 5

and 6c) for 2 h. The solvent was evaporated and the crude obtained was triturated and

washed with acetone to yield the methylated SiPc (1 or 2a-c).

Bis(hydroxyl)-octamethylated SiPc (1). 87% yield. Dark green solid. 1H NMR (300 MHz,

DMSO-d 6 , ppm): 9.80 (s, 8H, H3), 9.37 (s, 8H, H2), 8.96 (d, J = 6.0 Hz, 8H, H3),

8.67 (dd, J = 6.6 ,1.7 Hz, 8H, H5), 8.31 (m, 8H, H4), 4.43 (s, 24H, H1). 13C NMR (75

MHz, DMSO-d 6 , ppm): 155.3, 148.9, 147.7, 142.2, 137.7, 133.9, 132.9, 129.4, 128.9,

116.6, 77.6, 77.1, 76.7, 48.8. MS (ESI): m/z = 691.10 [M 3I]3+, 486.58 [M 4I]4+,

364.33 [M 5I]5+, 281.32 [M 6I]6+, 224.24 [M 7I]7+, 179 [M 8I]8+. HR-MS (ESI):

Calc. for C 72 N 16 SiO 10 H 42 I 5 C 8 H 24 : 691.3380, Found: 691.3315 Calc. for

C 72 N 16 SiO 10 H 42 I 4 C 8 H 24 : 486.7774, Found: 486.7776. UVVIS (H 2 O): max (nm) (log

): 675 (5.25), 646 (4.40), 608 (4.43), 356 (4.84). FT-IR (neat) (cm-1): 3382 (OH),

1581, 1497, 1451, 1415, 1262, 1083, 844 (SiO). Mp: 252 C.

1
H-NMR (500 MHz, 298K, DMSO-d 6 ) of 1

13
C-NMR (125 MHz, 298K, DMSO-d 6 ) of 1

Bis(triisobutylsilyl)-octamethylated SiPc (2a). 95% yield. Dark green solid. 1H NMR

(300 MHz, DMSO-d 6 , ppm): 9.77 (s, 8H, H3), 9.44 (s, 8H, H2), 9.02 (d, J = 5.9 Hz,

8H, H3), 8.59 (d, J = 8.8 Hz, 8H, H5), 8.34 (m, 8H, H4), 4.49 (s, 24H, H1) , -0.43 (d,

J = 6.4 Hz, 36H, H3 ), -0.80 (m, 6H, H2), -2.47 (d, J = 7.0 Hz, 12H, H1). 13C

NMR (75 MHz, DMSO-d 6 , ppm): 162.1, 155.5, 147.4, 147.3, 145.4, 143.1, 141.5,
141.0, 136.4, 135.9, 133.4, 128.9, 128.8, 126.1, 125.1, 48.3, 35.6, 30.6. MS (ESI): m/z =

1298.13 [M 2I]2+, 823.12 [M 3I]3+, 585.62 [M 4I]4+, 443.12 [M 5I]5+, 349.29 [M

6I]6+, 229.49 [M 8I]8+. HR-MS (ESI): Calc. for C 104 H 118 N 16 O 10 Si 3 I 5 : 823.1244,

Found: 823.1264. Calc. for C 104 H 118 N 16 O 10 Si 3 I 4 : 585.6170, Found: 585.6247. Calc. for

C 104 H 118 N 16 O 10 Si 3 I 3 : 443.1126, Found: 443.1228. Calc. for C 104 H 118 N 16 O 10 Si 3 I 2 :

348.1097, Found: 348.1191. Calc. for C 104 H 118 N 16 O 10 Si 3 : 229.3560, Found: 229.3623.

UV-VIS (H 2 O): max (nm) (log ): 675 (5.34), 646 (4.45), 608 (4.49), 356 (4.90). FT-IR

(neat) (cm-1): 1582, 1497, 1452, 1417, 1262, 1083. Mp: 232 C.

1
H-NMR (500 MHz, 298K, DMSO-d 6 ) of 2a

13
C-NMR (125 MHz, 298K, DMSO-d 6 ) of 2a
Bis(n-butylsilyl)-octamethylated SiPc (2b). 94% yield. Dark green solid. 1H NMR (300

MHz, CDCl 3 , ppm): 9.64 (s, 8H, H3), 9.32 (s, 8H, H2), 8.88 (d, J = 6.0, 8H, H3), 8.44

(dd, J = 7.0, 1.3 Hz, 8H, H5), 8.20 (m, 8H, H4), 4.35 (s, 24H, H1) , -0.01 (m, 30H,

H3-4), -1.38 (m, 12H, H2), -2.56 (m, 12H, H1). 13C NMR (75 MHz, DMSO-

d 6 , ppm): 162.2, 155.5, 148.1, 147.5, 141.5, 136.5, 133.7, 133.5, 128.9, 117.0, 48.4,

35.7, 30.6. MS (ESI): m/z = 1298.13 [M 2I]2+, 823.13 [M 3I]3+, 585.62 [M 4I]4+,

443.12 [M 5I]5+, 348.28 [M 6I]6+, 229.48 [M 8I]8+. HR-MS (ESI): Calc. for

C 104 H 118 N 16 O 10 Si 3 I 5 : 823.1244, Found: 823.1271. Calc. for C 104 H 118 N 16 O 10 Si 3 I 4 :

585.6170, Found: 585.6252. Calc. for C 104 H 118 N 16 O 10 Si 3 I 3 : 443.1126, Found: 443.1231.

Calc. for C 104 H 118 N 16 O 10 Si 3 I 2 : 348.1097, Found: 348.1194. Calc. for

C 104 H 118 N 16 O 10 Si 3 : 229.3560, Found: 229.3629. UV-VIS (H 2 O): max (nm) (log ): 673

(5.34), 643 (4.47), 606 (4.51), 356 (4.91). FT-IR (neat) (cm-1): 2997, 2920, 1584, 1500,

1454, 1419, 1284, 1174, 1085, 1023. Mp: 230 C.

1
H-NMR (500 MHz, 298K, DMSO-d 6 ) of 2b
 13
C-NMR (125 MHz, 298K, DMSO-d 6 ) of 2b

Bis(triphenylsilyl)-octamethylated SiPc (2c). 91% yield. Dark green solid. 1H NMR (300

MHz, DMSO-d 6 , ppm): 9.65 (s, 8H, H3), 9.48 (s, 8H, H2), 9.05 (d, J = 6.0 Hz, 8H,

H3), 8,68 (dd, J = 6.9 ,2.0 Hz, 8H, H5), 8.40 (m, 8H, H4), 6.92 (t, J = 7.4 Hz, 6H,

H4) , 6.55(t, J = 7.4 Hz, 12H, H3), 4.72 (d, 6.9 Hz, 12H, H2), 4.51 (s, 24H,

H1). 13C NMR (75 MHz, DMSO-d 6 , ppm): 155.3, 148.9, 147.7, 142.2, 137.7, 133.9,

132.9, 132.1, 129.4, 128.9, 126.9, 116.6, 77.6, 77.1, 76.7, 48.8. MS (ESI): m/z = 1358.53

[M 2I]2+, 863.06 [M 3I]3+, 615.82 [M 4I]4+. HR-MS (ESI): [M 2I]2+ Calcd. for

C 108 H 70 N 16 O 10 Si 3 I 6 C 8 H 24 : 1358.5458; Found: 1358.5832. UV-VIS (H 2 O): max (nm)

(log ): 679 (5.20), 648 (4.38), 611 (4.38), 355 (4.70). FT-IR (neat) (cm-1): 2998, 1582,

1498, 1454, 1418, 1283, 1175, 1085, 1036, 955, 886, 760. Mp: 207 C.

1
H-NMR (500 MHz, 298K, DMSO-d 6 ) of 2c

13
C-NMR (125 MHz, 298K, DMSO-d 6 ) of 2c
 2. Photophysical properties

5
1 6a

Norm. abs. / a.u.

6b
0.8 6c
0.6
0.4
0.2
0
300 400 500 600 700 800
Wavelength / nm

Figure S1. Electronic absorption spectra of the neutral SiPcs 5 and 6a-c in DMF

Figure S2. Absorption spectra of compound 2c upon partition between the PBS (blue) and 1-octanol (red)
phases, as a representative example of the behaviour of all described SiPc compounds (1 and 2a-c) in
partition coefficient experiments.
Figure S3. UV-vis dilution studies of the octacationic SiPcs 2a-c in physiologically relevant medium

(PBS buffer, pH 6.8).

3. Photochemical properties

1,2 0 sec
1,05
20 sec
1 40 sec
Absorption DPBF / a.u.

1
60 sec
A DPBF/ a.u.

0,95 R = 0,9996
0,8 80 sec
0,9

0,85
0,6
0,8
0 20 40 60 80
0,4 Irradiation time / sec

0,2

0
350 400 450 500 550 600 650 700 750
Wavelength / nm

Figure S4. Rate of photodegradation of a DPBF (414 nm) as caused by irradiation of SiPc 1, which is

directly proportional to the amount of formation of 1O 2 .

 4. References

[1] Li H, Jensen TJ, Fronczek FR, Vicente MG. Syntheses and properties of a series of cationic
water-soluble phthalocyanines. J Med Chem. 2008;51:502-11.