4 [(1,3 Dioxo 2,3 di­hydro 1H isoindol 2 yl)meth­yl]phthalo­nitrile

organic papers

Acta Cryst.(2005). E61, o3145–o3146 doi:10.1107/S1600536805027443 Xuet al. _C

17H9N3O2

o3145

Acta Crystallographica Section E Structure Reports

Online

ISSN 1600-5368

4-[(1,3-Dioxo-2,3-dihydro-1

H

-isoindol-2-yl)methyl]-phthalonitrile

Xiu-Zhi Xu, Mei-Jin Lin, Jun-Dong Wang,* Nai-Sheng Chen and Jin-Ling Huang

Department of Chemistry, University of Fuzhou, Fuzhou 350002, People’s Republic of China, and State Key Laboratory of Structural Chem-istry, Fujian Institute of Research on the Structure of Matter, Fuzhou 350002, People’s Republic of China

Correspondence e-mail: wangjd@fzu.edu.cn

Key indicators

Single-crystal X-ray study

T= 298 K

Mean(C–C) = 0.003 A˚

Rfactor = 0.037

wRfactor = 0.117

Data-to-parameter ratio = 13.2

For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.

#2005 International Union of Crystallography Printed in Great Britain – all rights reserved

In the title compound, C17H9N3O2, the phthalonitrile group

and the isoindole-1,3-dione group lie in approximately orthogonal planes and exhibit a dihedral angle of 92.76 (8)_.

Partial face-to-face overlap is observed between the two groups. In addition, the crystal packing is stabilized by C— H O and C—H N interactions.

Comment

The title compound, (I), is a precursor for the synthesis of amphiphilic phthalocyanine, which is utilized in the photo-dynamic therapy (PDT) of tumors (Huanget al., 2000). After phthalocyanine is formed, the phthalimide is easily converted to an amine, which is believed to have a better interaction with cell tissues. In the structure of a similar precursor (Zhuet al., 2005), the two groups are connected by a flexible butoxy chain. The difference between the earlier structure and (I) is that there is no O atom linked to the phthalocyanine ring, and we are investigating if this O atom will or will not influence the yield of active1O2in PDT (Kobayashiet al., 2003).

The molecular structure of (I) is shown in Fig. 1. The cyano-group N1—C7 [1.130 (3) A˚ ] and N2—C8 bonds [1.137 (3) A˚] are short enough to indicate their triple-bond character, and agree with the values reported by Zhuet al.(2005). The C1— C7 [1.436 (3) A˚ ] and C2—C8 [1.435 (3) A˚] bond distances are comparable to the mean value in phthalonitrile, 1.443 (8) A˚ , reported by Allen et al. (1987). The benzene ring of the phthalonitrile group and the isoindole ring system are essen-tially perpendicular to each other, with an angle of 92.76 (8)_.

In the crystal packing, the molecules are stacked along the short a axis with weak – interactions due to the partial overlap of the C1–C6 benzene rings and the isoindole ring systems, with perpendicular distances of 3.556 and 3.150 A˚ ,

respectively. In addition, the molecular packing is stabilized by C—H O and C—H N interactions (Table 1).

Experimental

4-Methylphthalic anhydride (50 g, 308 mmol) and urea (18.5 g, 308 mmol) were mixed and heated to 433 K; the mixture melted then solidified. The solid was washed with water and vacuum dried at 353 K to give 4-methylphthalimide (yield 87%, 43.5 g; m.p. 470.8– 471.4 K). All of the 4-methylphthalimide obtained was suspended in methanol (800 ml) and stirred for 5–7 days at room temperature while ammonia gas was pumped into the vessel. As the reaction progressed, the suspension dissolved and then a new suspension formed. After filtering and drying at 343 K, 4-methylphthalic diamide was obtained (yield 30%, 12 g; m.p. 455.4–455.6 K). 4-Methylphthalic diamide (10 g, 56.1 mmol) was suspended in pyridine (150 ml) and POCl3 (13 ml, 142 mmol) was added dropwise at 276–278 K. The

mixture was stirred at room temperature for 3 h and then poured into ice water; the precipitate was filtered off, washed with water and dried at 353 K, and 4-methylphthalonitrile was obtained (yield 60%, 4.6 g; m.p. 391.5–391.6 K). This was suspended in CCl4(70 ml), and thenN

-bromosuccimide (5.8 g, 32.6 mmol) and benzoyl peroxide (0.1–0.2 g) were added. The suspension was refluxed for 24 h, and then cooled to room temperature and filtered; the CCl4was evaporated and crude

bromomethylphthalonitrile (3.5 g) was obtained. The crude 4-bromomethylphthalonitrile (3.5 g, 15.8 mmol), phthalimide (2.4 g, 16.3 mmol) and K2CO3 (5 g, 36.2 mmol) were added to N,N

-dimethylformamide (60 ml), and then stirred at 353 K for 12 h. The reaction mixture was poured into ice water (800 ml), and the preci-pitate was separated by centrifugation, washed with water and vacuum dried at 353 K, resulting in crude (I) (1.7 g). The crude (I) was washed with CH3OH and recrystallized from tetrahydrofuran

and CH2Cl2repeatedly; colorless needle-shaped crystals of (I) were

obtained (m.p. 550–551 K). MS (m/z, %): 287 (M+, 100); IR (KBr, cm1): 2229 (C—N), 3069 (Ar—H), 1706 (C–O), 1776, 1420 (–CH2–),

1390, 1112 (N—H), 951 (C—H), 724; UV–vis: 227.41, 294.02 nm (CH2Cl2), 235.04, 284.18, 293.95 nm (THF);

1

H NMR (DMSO-d6):

4.919 (s, 2H), 7.910 (br, 5H), 8.115 (d, 1H), 8.183 (s, 1H).

Crystal data

C17H9N3O2 Mr= 287.27

Monoclinic,P21=c a= 4.9331 (3) A˚

b= 26.2490 (13) A˚

c= 10.4901 (6) A˚

= 93.0930 (13) V= 1356.37 (13) A˚3 Z= 4

Dx= 1.407 Mg m

3

MoKradiation Cell parameters from 6576

reflections

= 6.1–54.9

= 0.10 mm1 T= 298 (2) K Needle, colorless 0.700.100.08 mm

Data collection

Rigaku R-AXIS RAPID diffractometer

!scans

11806 measured reflections 3107 independent reflections 1558 reflections withI> 2(I)

Rint= 0.044

max= 27.5

h= 0!6

k= 0!34

l=13!13

Refinement

Refinement onF2 R[F2_{> 2(F}2_{)] = 0.037} wR(F2) = 0.117

S= 1.00 3107 reflections 235 parameters

All H-atom parameters refined

w= 1/[2_(F

o2) + (0.042P)2]

whereP= (Fo2+ 2Fc2)/3

(/)max< 0.001

max= 0.14 e A˚

3

min=0.23 e A˚

3

Table 1

Hydrogen-bond geometry (A˚ ,_).

D—H A D—H H A D A D—H A

C3—H1 O2i

0.91 (2) 2.47 (2) 3.275 (3) 148 (2) C6—H3 N2ii

0.95 (2) 2.60 (2) 3.280 (3) 129 (2) C15—H9 O1iii 0.97 (2) 2.44 (2) 3.378 (3) 161 (2)

Symmetry codes: (i)x1;y;z; (ii)xþ1;yþ1 2;z

1

2; (iii)x;yþ1;zþ1.

All H atoms were located in a difference Fourier map and refined isotropically. The C—H distances lie in the range 0.89 (2)–1.01 (3) A˚ . Data collection:RAPID-AUTO (Rigaku, 1998); cell refinement:

RAPID-AUTO; data reduction:RAPID-AUTO; program(s) used to solve structure: SHELXS97(Sheldrick, 1997); program(s) used to refine structure:SHELXL97(Sheldrick, 1997); molecular graphics:

ORTEX (McArdle, 1995); software used to prepare material for publication:SHELXL97.

This work was supported by the Science Foundation of Fujian Province (No. E0310007) and the Science and Tech-nology Developing Foundation of Fuzhou University (No. 2004-XQ-10).

References

Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & Taylor, R. (1987).J. Chem. Soc. Perkin Trans. 2. pp. S1–19.

Huang, J. L., Chen, N. S., Huang, J. D., Liu, E. S., Xue, J. P., Yang, S. L., Huang, Z. Q. & Sun, J. C. (2000).Sci China Ser. B,30, 481–488.

Kobayashi, N., Ogata, H., Nonaka, N. & Luk’yanets, E. A. (2003).Chem. Eur. J.9, 5123–5134.

McArdle, P. (1995).J. Appl. Cryst.28, 65.

Rigaku (1998).RAPID-AUTO. Version 1.06. Rigaku Corporation, Tokyo, Japan.

Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Go¨ttingen, Germany.

Zhu, X.-L., Lin, M.-J., Wang, J.-D., Chen, N.-S. & Huang, J.-L. (2005).Acta Cryst.E61, o1214–o1215.

Figure 1

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supporting information

Acta Cryst. (2005). E61, o3145–o3146 [doi:10.1107/S1600536805027443]

4-[(1,3-Dioxo-2,3-dihydro-1

H

-isoindol-2-yl)methyl]phthalonitrile

Xiu-Zhi Xu, Mei-Jin Lin, Jun-Dong Wang, Nai-Sheng Chen and Jin-Ling Huang

S1. Comment

The title compound, (I), is a precursor for the synthesis of amphiphilic phthalocyanine, which is utilized in the photodynamic therapy (PDT) of tumors (Huang et al., 2000). After phthalocyanine is formed, the phthalimide is easily converted to an amine, which is believed to have a better interaction with cell tissues. In the structure of a similar precursor (Zhu et al., 2005), the two groups are connected by a flexible butoxy chain. The difference between the earlier structure and (I) is that there is no O atom linked to the phthalocynine ring, and we are investigating if this O atom will or will not influence the yield of active 1_O

2 in PDT (Kobayashi et al., 2003).

The molecular structure of (I) is shown in Fig. 1. The cyano-group N1—C7 [1.130 (3) Å] and N2—C8 bonds [1.137 (3) Å] are short enough to indicate their triple-bond character, and agree with the values reported by Zhu et al. (2005). The C1—C7 [1.436 (3) Å] and C2—C8 [1.435 (3) Å] bond distances are comparable to the mean value of phthalonitrile, 1.443 (8) Å, reported by Allen et al. (1987). The benzene ring of the phthalonitrile group and the isoindole ring system are perpendicular to each other, with an angle of 92.76 (8)°.

In the crystal packing, the molecules are stacked along the short a axis with weak π–π interactions due to the partial overlap of the C1–C6 benzene rings and the isoindole ring systems, with perpendicular distances of 3.556 and 3.150 Å, respectively. In addition, the molecular packing is stabilized by C—H···O and C—H···N interactions (Table 1).

S2. Experimental

4-Methylphthalic anhydride (50 g, 308 mmol) and urea (18.5 g, 308 mmol) were mixed and heated to 433 K; the mixture melted then solidified. The solid was washed with water and vacuum dried at 353 K to give 4-methylphthalimide (yield 87%, 43.5 g; m.p. 470.8–471.4 K). All of the 4-methylphthalimide obtained was suspended in methanol (800 ml) and stirred for 5–7 days at room temperature while ammonia gas was pumped into the vessel. As the reaction progressed, the suspension dissolved and then a new suspension formed. After filtering and drying at 343 K, 4-methylphthalic diamide was obtained (yield 30%, 12 g; m.p. 455.4–455.6 K). 4-Methylphthalic diamide (10 g, 56.1 mmol) was suspended in pyridine (150 ml) and POCl3 (13 ml, 142 mmol) was added dropwise at 276–278 K. The mixture was stirred at room

temperature for 3 h and then poured into ice water; the precipitate was filtered off, washed with water and dried at 353 K, and 4-methylphthalonitrile was obtained (yield 60%, 4.6 g; m.p. 391.5–391.6 K). This was suspended in CCl4 (70 ml),

and then N-bromosuccimide (5.8 g, 32.6 mmol) and benzoyl peroxide (0.1–0.2 g) were added. The suspension was refluxed for 24 h, and then cooled to room temperature and filtered; the CCl4 was evaporated and crude

4-bromomethyl-phthalonitrile (3.5 g) was obtained. The crude 4-bromomethyl4-bromomethyl-phthalonitrile (3.5 g, 15.8 mmol), phthalimide (2.4 g, 16.3 mmol) and K2CO3 (5 g, 36.2 mmol) were added to N,N-dimethylformamide (60 ml), and then stirred at 353 K for 12 h.

The reaction mixture was poured into ice water (800 ml), and the precipitate was separated by centrification, washed with water and vacuum dried at 353 K, resulting in crude (I) (1.7 g). The crude (I) was washed with CH3OH and recrystallized

(m/z, %): 287 (M+_{, 100); IR (KBr, cm}−1_{): 2229 (C—N), 3069 (Ar—H), 1706 (C–O), 1776, 1420 (–CH}

2–), 1390, 1112 (N

—H), 951 (C—H), 724; UV–vis: 227.41, 294.02 nm (CH2Cl2), 235.04, 284.18, 293.95 nm (THF); 1H NMR (DMSO-d6):

δ 4.919 (s, 2H), 7.910 (br, 5H), 8.115 (d, 1H), 8.183 (s, 1H).

S3. Refinement

All H atoms were located in a difference Fourier map and refined isotropically. The C—H distances lie in the range 0.89 (2)–1.01 (3) Å.

Figure 1

The structure of (I), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 40% probability level.

4-[4-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phthalonitrile

Crystal data

C17H9N3O2

Mr = 287.27 Monoclinic, P21/c

Hall symbol: -P 2ybc

a = 4.9331 (3) Å

b = 26.2490 (13) Å

c = 10.4901 (6) Å

β = 93.0930 (13)°

V = 1356.37 (13) Å3

Z = 4

F(000) = 592

Dx = 1.407 Mg m−3

Melting point: 550 K

Mo Kα radiation, λ = 0.71069 Å Cell parameters from 6576 reflections

θ = 6.1–54.9°

µ = 0.10 mm−1

T = 298 K Needle, colourless 0.70 × 0.10 × 0.08 mm

Data collection

Rigaku R-AXIS RAPID diffractometer

Radiation source: Rotating anode

Graphite Monochromator monochromator

ω scans

11806 measured reflections 3107 independent reflections

1558 reflections with I > 2σ(I)

Rint = 0.044

θmax = 27.5°, θmin = 1.6°

h = 0→6

k = 0→34

l = −13→13

Refinement

Refinement on F2

Least-squares matrix: full

R[F2 _{> 2σ(F}2_{)] = 0.037}

wR(F2_{) = 0.117}

S = 1.00

3107 reflections 235 parameters 0 restraints

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Secondary atom site location: difference Fourier map

Hydrogen site location: difference Fourier map All H-atom parameters refined

w = 1/[σ2_(F

o2) + (0.042P)2]

where P = (Fo2 + 2Fc2)/3

(Δ/σ)max < 0.001

Δρmax = 0.14 e Å−3

Δρmin = −0.23 e Å−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 _{against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F}2_,

conventional R-factors R are based on F, with F set to zero for negative F2_{. The threshold expression of F}2 _{> σ(F}2_{) is used}

only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2

are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2₎

x y z Uiso*/Ueq

C17 0.7488 (5) 0.45506 (8) 0.7767 (2) 0.0452 (5)

Atomic displacement parameters (Å2₎

U11 _U22 _U33 _U12 _U13 _U23

O1 0.0690 (12) 0.0635 (10) 0.0591 (11) 0.0001 (9) −0.0150 (10) −0.0092 (8) N3 0.0472 (10) 0.0382 (9) 0.0425 (10) −0.0015 (9) 0.0045 (9) −0.0008 (8) O2 0.0583 (11) 0.0651 (10) 0.0642 (11) 0.0162 (9) −0.0093 (9) −0.0038 (9) N2 0.0887 (17) 0.0611 (13) 0.0777 (16) −0.0039 (12) 0.0414 (14) 0.0014 (11) N1 0.105 (2) 0.0569 (13) 0.0849 (18) −0.0153 (14) 0.0165 (15) 0.0083 (13) C1 0.0510 (13) 0.0399 (12) 0.0490 (13) −0.0011 (10) 0.0045 (11) −0.0004 (10) C2 0.0424 (12) 0.0428 (12) 0.0415 (13) −0.0004 (10) 0.0053 (10) 0.0008 (9) C3 0.0470 (13) 0.0386 (12) 0.0427 (13) 0.0048 (11) 0.0072 (10) −0.0027 (10) C4 0.0415 (12) 0.0402 (12) 0.0400 (12) 0.0000 (10) 0.0022 (10) −0.0026 (9) C5 0.0522 (14) 0.0462 (13) 0.0500 (14) 0.0037 (11) 0.0157 (12) −0.0058 (11) C6 0.0643 (16) 0.0392 (13) 0.0588 (16) 0.0045 (12) 0.0134 (13) −0.0065 (11) C7 0.0671 (17) 0.0448 (13) 0.0583 (15) −0.0030 (13) 0.0086 (13) 0.0006 (12) C8 0.0570 (15) 0.0434 (13) 0.0543 (15) −0.0022 (11) 0.0148 (13) 0.0017 (11) C9 0.0534 (16) 0.0426 (12) 0.0508 (15) −0.0008 (12) 0.0140 (12) −0.0033 (11) C10 0.0431 (13) 0.0399 (11) 0.0422 (13) −0.0052 (10) 0.0062 (10) 0.0025 (9) C11 0.0436 (13) 0.0408 (11) 0.0419 (13) −0.0042 (10) 0.0063 (11) 0.0001 (10) C12 0.0558 (16) 0.0591 (16) 0.0497 (15) −0.0042 (13) −0.0038 (13) −0.0066 (12) C13 0.0754 (18) 0.0484 (14) 0.0617 (17) −0.0015 (14) 0.0057 (15) −0.0138 (13) C14 0.0634 (17) 0.0422 (13) 0.0679 (17) 0.0046 (13) 0.0071 (14) −0.0020 (12) C15 0.0521 (14) 0.0475 (13) 0.0532 (15) 0.0026 (12) 0.0042 (12) 0.0059 (11) C16 0.0466 (13) 0.0457 (12) 0.0429 (13) −0.0063 (11) 0.0049 (11) 0.0035 (10) C17 0.0445 (13) 0.0484 (12) 0.0432 (13) −0.0016 (11) 0.0065 (11) 0.0032 (10)

Geometric parameters (Å, º)

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C17—N3—C16 111.94 (17) C4—C9—H5 105.4 (14) C17—N3—C9 124.89 (19) H4—C9—H5 111 (2) C16—N3—C9 123.16 (19) C15—C10—C11 121.8 (2) C6—C1—C2 118.9 (2) C15—C10—C16 130.1 (2) C6—C1—C7 121.4 (2) C11—C10—C16 108.11 (18) C2—C1—C7 119.7 (2) C12—C11—C10 121.0 (2) C3—C2—C1 120.1 (2) C12—C11—C17 130.8 (2) C3—C2—C8 120.42 (19) C10—C11—C17 108.11 (18) C1—C2—C8 119.50 (19) C11—C12—C13 117.6 (2) C2—C3—C4 121.0 (2) C11—C12—H6 120.6 (15) C2—C3—H1 118.8 (13) C13—C12—H6 121.8 (15) C4—C3—H1 120.3 (13) C12—C13—C14 121.4 (2) C3—C4—C5 118.5 (2) C12—C13—H7 120.2 (15) C3—C4—C9 122.34 (19) C14—C13—H7 118.4 (14) C5—C4—C9 119.1 (2) C13—C14—C15 121.3 (2) C6—C5—C4 121.2 (2) C13—C14—H8 120.0 (15) C6—C5—H2 118.8 (13) C15—C14—H8 118.6 (15) C4—C5—H2 120.0 (13) C10—C15—C14 116.9 (2) C5—C6—C1 120.4 (2) C10—C15—H9 124.3 (13) C5—C6—H3 121.5 (13) C14—C15—H9 118.7 (13) C1—C6—H3 118.1 (13) O1—C16—N3 124.1 (2) N1—C7—C1 178.6 (3) O1—C16—C10 130.0 (2) N2—C8—C2 179.6 (3) N3—C16—C10 105.91 (18) N3—C9—C4 114.01 (18) O2—C17—N3 124.4 (2) N3—C9—H4 110.2 (13) O2—C17—C11 129.6 (2) C4—C9—H4 107.9 (13) N3—C17—C11 105.92 (19) N3—C9—H5 107.9 (14)

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A

C3—H1···O2i _{0.91 (2) 2.47 (2) 3.275 (3) 148.4 (17)}

C6—H3···N2ii _{0.95 (2) 2.60 (2) 3.280 (3) 128.6 (16)}

C15—H9···O1iii _{0.97 (2) 2.44 (2) 3.378 (3) 160.7 (17)}