Coordination and peri-Carbon Metalation of 1-Nitro-9-[(2-aminoethyl)amino]acridines toward Platinum(II). Evidences for Hydrogen Bonding between Endocyclic N(10)H and Chloride Ion

Article abstract of DOI:10.1021/ic950804t

The antitumor drugs 1-nitro-9-[(2-(dialkylamino)ethyl)amino]acridines (alkyl = Me, A₁; Et, A₂) with platinum-(II) give tridentate coordination compounds in which the two nitrogens of the ethylenediamine side chain and the C(8) carbon atom of the acridine ring system act as donor atoms. An excess of triphenylphosphine displaces the residual chloride coordinated to platinum but leaves unaltered the tridentate acridine ligand. The structures of [Pt(A₁-H)Cl], 1, and [Pt(A₁-H)(PPh₃)]Cl, 3, have been solved by single-crystal X-ray diffraction. 1·CHCl₃ crystallizes in the orthorhombic system, space group P2₁2₁2₁ (no. 19), with a = 8.715(1) A?, b = 11.045(2) A?, c = 22.609(4) A?, Z = 4, R = 0.0559, and R_w = 0.0561 for 1502 reflections with F > 3σ(F). 3·1/2CH₂Cl₂ crystallizes in the monoclinic system, space group P2₁/c (no. 14), with a = 13.418(3) A?, b = 14.053(3) A?, c = 18.918(4) A?, β = 97.21(3)°, Z = 4, R = 0.0591, and R_w = 0.0611 for 3608 reflections with F > 4σ(F). In both complexes the acridine ligand adopts an imino-type configuration with the proton of the exocyclic 9-amino group shifted on N(10). Because of a severe steric interaction between the nitro group in the 1-position and the chelate diamine chain in the 9-position, the acridine moiety is folded about the C(9)-N(10) vector with an average angle between outer rings of 12°. Moreover, the acridine aromatic moiety and the platinum coordination planes are twisted, forming a dihedral angle of ca. 20°. The steric repulsion between the nitro and the diamine groups appears to provide the driving force to metalation. The H(10) proton has a great tendency to be engaged in H-bonding as shown by X-ray and solution studies. The formation of a H-bond with a rather poor acceptor such as the chloride ion can cause a downfield shift of the H-resonance as large as 6 ppm.

Full text of DOI:10.1021/ic950804t

876
Inorg. Chem. 1996, 35, 876-882
Coordination and peri-Carbon Metalation of 1-Nitro-9-[(2-aminoethyl)amino]acridines
toward Platinum(II). Evidences for Hydrogen Bonding between Endocyclic N(10)H and
Chloride Ion
Edmondo Ceci,† Renzo Cini,‡ Jerzy Konopa,§ Luciana Maresca,† and Giovanni Natile*,†
Dipartimento Farmaco-Chimico, Universita` di Bari, via E. Orabona 4, 70125 Bari, Italy,
Dipartimento di Chimica, Universita` di Siena, Pian dei Mantellini 44, 53100 Siena, Italy, and
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk,
Narutowicza St 11, 80952 Gdansk, Poland
ReceiVed June 29, 1995X
The antitumor drugs 1-nitro-9-[(2-(dialkylamino)ethyl)amino]acridines (alkyl ) Me, A1; Et, A2) with platinum-
(II) give tridentate coordination compounds in which the two nitrogens of the ethylenediamine side chain and the
C(8) carbon atom of the acridine ring system act as donor atoms. An excess of triphenylphosphine displaces the
residual chloride coordinated to platinum but leaves unaltered the tridentate acridine ligand. The structures of
[Pt(A1-H)Cl], 1, and [Pt(A1-H)(PPh3)]Cl, 3, have been solved by single-crystal X-ray diffraction. 1‚CHCl3
crystallizes in the orthorhombic system, space group P212121 (no. 19), with a ) 8.715(1) Å, b ) 11.045(2) Å, c
) 22.609(4) Å, Z ) 4, R ) 0.0559, and Rw ) 0.0561 for 1502 reflections with F > 3σ(F). 3‚1/2CH2Cl2 crystallizes
in the monoclinic system, space group P21/c (no. 14), with a ) 13.418(3) Å, b ) 14.053(3) Å, c ) 18.918(4) Å,
â ) 97.21(3)°, Z ) 4, R ) 0.0591, and Rw ) 0.0611 for 3608 reflections with F > 4σ(F). In both complexes
the acridine ligand adopts an imino-type configuration with the proton of the exocyclic 9-amino group shifted on
N(10). Because of a severe steric interaction between the nitro group in the 1-position and the chelate diamine
chain in the 9-position, the acridine moiety is folded about the C(9)-N(10) vector with an average angle between
outer rings of 12°. Moreover, the acridine aromatic moiety and the platinum coordination planes are twisted,
forming a dihedral angle of ca. 20°. The steric repulsion between the nitro and the diamine groups appears to
provide the driving force to metalation. The H(10) proton has a great tendency to be engaged in H-bonding as
shown by X-ray and solution studies. The formation of a H-bond with a rather poor acceptor such as the chloride
ion can cause a downfield shift of the H-resonance as large as 6 ppm.
Introduction
retained by 4-nitro isomers).7 Data, so far collected, strongly
suggest that 1-nitro-9-(aminoalkyl)acridines undergo, in ViVo,
a metabolic activation which induces DNA cross-links and
single-strand breaks while parent compounds themselves do not
have such abilities.7,8 There have been, though, several studies
aimed to clarify the reasons for the unique behavior of 1-nitro-
9-(aminoalkyl)acridines with respect to other isomers.
These molecules can exist in two tautomeric forms, amino
and imino, depending upon the presence of a proton either on
(C9)N or on N(10), and the composition of equilibrium changes
with the position of the nitro substituent.
The biological activity of acridines (essentially as antibacterial
and antimalaric agents) has been known for many decades.1
More recently, new interest has grown over these molecules
since 1-nitro-9-(aminoalkyl)acridines possess anticancer proper-
ties,2 and one of them, namely 1-nitro-9-[(3-(dimethylamino)-
propyl)amino]acridine (commercial names: nitracrine and
ledakrine), has also been used in clinical therapy.2a,3 Nitracrine
proved also to have potent hypoxia selective cytotoxicity in
Vitro,4 and some substituted analogues showed hypoxia selective
cytotoxicity also in ViVo.5
When the nitro substituent shifts from the 1-position to
another ring position (2, 3, or 4), the nitroaminoacridines lose
their antitumor activity6 (hypoxia selective cytotoxicity is
† Universita` di Bari.
‡ Universita` di Siena.
§ Technical University of Gdansk.
X Abstract published in AdVance ACS Abstracts, January 15, 1996.
(1) Acheson, R. M. Acridines, 2nd ed.; Interscience: New York, 1973.
(2) (a) Radzikowski, C.; Ledochowski, A.; Hrabowska, M.; Horowska,
B.; Stefanska, B.; Konopa, J.; Morowska, E. Arch. Immunol. Ther.
Exp. 1969, 17, 99. (b) Radzikowski, C.; Ledochowski, A.; Hrabowska,
M.; Stefanska, B.; Horowska, B.; Konopa, J.; Morowska, E.; Urbanska,
M. Arch. Immunol. Ther. Exp. 1969, 19, 219.
The results of several X-ray studies9 carried out on nitro-9-
(aminoalkyl)acridines did show that the nitro group in the
1-position of the acridine ring system interacts strongly with
the side chain in the 9-position, causing a folding of the acridine
plane about the C(9)-N(10) vector (dihedral angle between
outer rings of 13-22°) and preference for the imino-type
(3) Ledochowski, A. Zesz. Nauk. Politech. Gdansk., Chem. 1966, 14, 3.
Ledochowski, A.; Stefanska, B. Rocz. Chem. 1966, 14, 3.
(4) Wilson, W. R.; Denny, W. A.; Twigden, S. J.; Baguley, B. C.; Probert,
J. C. Br. J. Cancer 1984, 49, 215.
(5) Wilson, W. R.; Thompson, L. H.; Anderson, R. F.; Denny, W. A. J.
Med. Chem. 1989, 32, 31.
(7) Boyd, M.; Denny, W. A. J. Med. Chem. 1990, 33, 2656.
(8) (a) Pawlak, J. W.; Konopa, J. Biochem. Pharmacol. 1979, 28, 3391.
(b) Pawlak, K.; Matuszkiewicz, A.; Pawlak, J. W.; Konopa, J. Chem.
Biol. Interact. 1983, 43, 131. (c) Pawlak, K.; Pawlak, J. W.; Konopa,
J. Chem. Biol. Interact. 1983, 43, 175. (d) Pawlak, K.; Pawlak, J. W.;
Konopa, J. Cancer Res. 1984, 44, 4289.
(6) Woynarowski, J. M.; Bartoszek, A.; Konopa, J. Chem. Biol. Interact.
1984, 49, 311.
0020-1669/96/1335-0876$12.00/0 © 1996 American Chemical Society

1-Nitro-9-[(2-aminoethyl)amino]acridines
Inorganic Chemistry, Vol. 35, No. 4, 1996 877
Table 1. Crystallographic Data for 1‚CHCl3 and 3‚1/2CH2Cl2
configuration. In contrast, the nitro substituent in the positions
2 and 3 ensures planarity of the acridine moiety and amino-
type configuration. In the imino tautomer the C(9)-N bond
order increases with respect to that of the amino tautomer, and
accordingly, the bond length becomes shorter.
Also in water solution, at physiological pH (7-8), 1-ni-
troacridines have the usual imino-type configuration while 2-
and 3-nitroacridines are again present in the amino form.10 The
lower pKa values observed for 1-nitroacridines as compared to
those of 2-, 3-, and 4-nitro isomers go along with their preference
for the imino tautomeric form.7
The presence of the imino tautomer appears to be relevant
to the biological activity of these molecules. Hypoxia selective
cytotoxicity is exhibited by 1- and 4-nitroacridines. In the latter
case, in which an equilibrium between imino and amino
tautomers is present, the cytotoxic activity appears to correlate
with the percentage of imino tautomer.11
1‚CHCl3
3‚1/2CH2Cl2
formula
a, Å
b, Å
C18H18Cl4N4O2Pt
8.715(1)
11.045(2)
22.609(4)
90
90
90
2176(1)
1.919
4
C35.5H33Cl2N4O2PPt
13.418(3)
14.053(3)
18.918(4)
90
97.21(3)
90
3539(2)
1.585
4
c, Å
R, deg
â, deg
γ, deg
V, Å3
F
Z
calcd, g‚cm-3
fw
628.6
P212121 (no. 19)
25
844.6
P21/c (no. 14)
25
space group
T, °C
λ, Å
0.71073
70.2
0.48, 0.93
0.0559
0.0561
0.71073
42.37
0.54, 0.96
0.0591
µ (Mo KR), cm-1
transm coeff
R(Fo)a
Rw(Fo)b
0.0611
A greater anticancer activity has been found when the side
chain in the 9-position bears a second amine functionality and
two or three methylene spacers are placed in between the two
nitrogens.6 The diamine chain, with the two nitrogen atoms
separated by two or three carbon spacers, is proposed to play a
crucial role in the metabolic activation of such a drug.
These acridines are also amenable to coordination studies
toward platinum. The diamine chain could act as a bidentate
ligand toward platinum; in this way a powerful alkylating agent
would be incorporated in the acridine molecule and a prelimi-
nary metabolic activation for its biological action could no
longer be required.12 Coordination to a metal atom is also likely
to induce variations in the amino-imino tautomerism.
In this paper we report on the synthesis and structural
characterization of some platinum(II) complexes with 1-nitro-
9-[(2-(dialkylamino)ethyl)amino]acridines.
b
a R(Fï) ) ∑|Fo - |Fc||/∑Fo. Rw(Fï) ) w|Fo - |Fc||/∑ w.
x
x
to prevent contact with moist air. During the reaction time, the [PtCl2-
(DMSO)2] progressively dissolved and a deep red color developed. An
excess of LiCl (2-3 mmol) was then added, and the mixture was kept
stirring for an additional 2 h (the need for this step is commented on
later in this section). The reaction solution was concentrated and then
chromatographed over a silica gel column. The first yellow fraction,
eluted with CH2Cl2, contained a few milligrams of the product of
hydrolysis of A1 to the corresponding 9-acridone. The main fraction
was eluted with dichloromethane containing 3% (v/v) acetone. Evapo-
ration to dryness under reduced pressure gave a dark red crystalline
solid [PtCl(A1-H)] which always contained some solvent of crystal-
lization. Small amounts of other products could be eluted using higher
contents of acetone (>10%, v/v), but they have not been identified at
this stage of the work. The yield of desired product was 60% relative
to platinum. Anal. Calcd for C17H17ClN4O2Pt‚1/2CH2Cl2: C, 36.1; H,
3.1; N, 9.6; Cl, 12.2. Found: C, 36.0; H, 3.2; N, 9.4; Cl, 12.0.
[PtCl(A2-H)], 2. Compound 2 was prepared in a similar way as 1.
In this case, however, the acridine, A2, was available as a dihydro-
chloride salt and the free base was formed in situ by addition of the
stoichiometric amount of LiOH. In spite of the water formed in the
neutralization reaction, the content of 9-acridone was almost as low as
that in the previous case (probably the formed LiCl did act as a drying
agent). Yield: 55%. Anal. Calcd for C19H21ClN4O2Pt‚1/2CH2Cl2: C,
38.4; H, 3.6 N, 9.2; Cl, 11.6. Found: C, 39.2; H, 3.9; N, 8.9; Cl,
11.2.
Experimental Section
Starting Materials. The complex [PtCl2(DMSO)2] was prepared
according to ref 13. Dry chlorinated solvents were obtained by
distillation from calcium hydride. 1-Nitro-9-[(2-(dimethylamino)ethyl)-
amino]acridine, A1, and 1-nitro-9-[(2-(diethylamino)ethyl)amino]acri-
dine, A2, were prepared according to ref 8b.
Preparation of Complexes. [PtCl(A1-H)], 1. Compound 1 was
prepared by reaction of [PtCl2(DMSO)2] with ligand A1 in dry CH2Cl2
(in a typical experiment 1 mmol of both reagents and 10 mL of solvent
were used). The mixture was refluxed for 4 h in an argon atmosphere
[Pt(A1-H)(PPh3)]Cl, 3. A 25 mg (0.04 mmol) sample of 1 was
dissolved in 3 mL of dichloromethane and treated with a 3-fold excess
of triphenylphosphine. The solution was kept stirring for 2 h at room
temperature. Meanwhile, a color change from violet-red to orange-
red took place. The solvent was evaporated under reduced pressure,
and the solid residue was repeatedly washed with pentane to remove
unreacted phosphine and then dried in Vacuo. It proved to be the
product of incorporation of one molecule of triphenylphosphine in 1;
the yield was quantitative. Anal. Calcd for C35H32ClN4O2Pt: C, 52.4;
H, 4.0; N, 7.0; Cl, 4.4. Found: C, 52.6; H, 4.1; N, 6.8; Cl, 4.1.
Physical Measurements. Infrared spectra were recorded as KBr
(in the range 4000-400 cm-1) or polythene pellets (in the range 400-
200 cm-1) on a Perkin-Elmer 283 spectrophotometer. Proton NMR
spectra were recorded on Varian XL 200 and Bruker AM 300 and AM
500 spectrometers.
X-ray Crystallography for 1. Crystals of 1 were grown from
CHCl3 solution. A well-formed red prism was selected for the X-ray
analysis. Crystallographic data are listed in Table 1. Unit cell
parameters were obtained by least-squares refinement of the values (in
the range 2θ ) 10-25°) of 28 carefully centered reflections chosen
from different regions of the reciprocal space. On the basis of the
systematic extinctions, the space group was selected as P212121. This
choice was in agreement with the analysis of the normalized structure
factors which indicated a non-centrosymmetric space group (|E2 - 1|
) 0.659, 0.736 for non-centrosymmetric space groups, and 0.968 for
(9) Dauter, Z.; Bogucka-Ledokowska, M.; Hempel, A.; Ledochowski, A.;
Kosturkiewic, Z. Rocz. Chem. 1975, 49, 859. Hempel, A.; Hull, S.
E.; Bogucka-Ledokowska, M.; Dauter, Z. Acta Crystallogr., Sect. B
1979, B35, 474. Hempel, A.; Hull, S. E.; Dauter, Z.; Bogucka-
Ledokowska, M.; Konitz, A. Acta Crystallogr., Sect. B 1979, B35,
477. Skonieczny, S.; Ledochowski, A. Heterocycles 1979, 4, 1693.
Stallings, W. C.; Glusker, J. P.; Carrell, H. L.; Stezowski, J. J.;
Bogucka-Ledokowska, M.; Ledochowski, A. J. Biomol. Struct. Dynam.
1984, 2, 511. Pett, V. B.; Rossi, M.; Glusker, J. P.; Stezowski, J. J.;
Bogucka-Ledokowska, M. Bioorg. Chem. 1982, 11, 443. Stezowski,
J. J.; Kollat, P.; Bogucka-Ledokowska, M.; Glusker, J. P. J. Am. Chem.
Soc. 1985, 107, 2067.
(10) The position of the tautomeric equilibrium is also influenced by the
solvent. In solvents of low polarity all nitroacridines have the aminic
conformation with the only exception of the 4-nitro isomer for which
an equilibrium between both tautomeric forms is found.7 Calculations
performed on different nitroisomers have assigned lower dipole
moment to the amino tautomer for all nitro isomers with the only
exception of the 4-nitro species. See: Tempczyk, A.; Rak, J.;
Blazejowski, J. J. Chem. Soc., Dalton Trans. 1990, 1501.
(11) Denny, A. J. Med. Chem. 1990, 33, 1288.
(12) Bowler, B. E.; Hollis, L. S.; Lippard, S. J. J. Am. Chem. Soc. 1984,
106, 6102. Bowler, B. E.; Lippard, S. J. Biochemistry 1986, 25, 3031.
Bowler, B. E.; Amhed, K. J.; Sundquist, W. I.; Hollis, L. S.; Whang,
E. E.; Lippard, S. J. J. Am. Chem. Soc. 1989, 111, 1299.
(13) Kukushkin, Yu. N.; Vyaz’menskii, Yu. E.; Zorina, L. I.; Pazukhina,
Yu. L. Russ. J. Inorg. Chem. (Engl. Transl.) 1968, 13, 835.

878 Inorganic Chemistry, Vol. 35, No. 4, 1996
Ceci et al.
Table 2. Fractional Atomic Coordinates (×104) for the
Non-Hydrogen Atoms of 1‚CHCl3
Table 3. Fractional Atomic Coordinates (×104) for the
a
Non-Hydrogen Atoms of 3‚1/2CH2Cl2
atom
x/a
y/b
z/c
atom
x/a
y/b
z/c
Pt
Cl
3682(1)
4011(6)
4610(1)
3594(5)
2342(1)
1458(2)
4141(7)
4912(7)
3128(6)
2705(8)
4473(8)
3199(7)
3164(94)
4356(8)
4864(10)
4798(11)
4234(9)
2133(10)
1619(11)
1636(10)
2167(8)
3225(8)
3779(8)
3734(8)
2686(10)
2702(8)
3557(9)
3161(9)
2958(11)
2271(11)
4441(5)
4708(9)
5572(4)
4845(13)
Pt
Cl
P
O(1)
O(2)
N(1)
N(2)
N(3)
C(11P)
C(21P)
C(31P)
C(41P)
C(51P)
C(61P)
C(12P)
C(22P)
C(32P)
C(42P)
C(52P)
C(62P)
C(13P)
C(23P)
C(33P)
C(43P)
C(53P)
C(63P)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
N(10)
H(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
Cl(1d)a
Cl(2d)a
C(d)a
2276(1)
9475(3)
3520(2)
1415(9)
-32(10)
1194(8)
1658(7)
3479(12)
4759(8)
4859(10)
5814(10)
6657(9)
6537(9)
5602(9)
3206(8)
2255(10)
1961(12)
2697(12)
3635(11)
3931(10)
3811(8)
3473(10)
3610(13)
4072(12)
4434(11)
4291(9)
-10(11)
-763(13)
-1110(12)
-639(9)
2028(10)
2768(9)
2931(9)
2406(8)
1062(8)
661(7)
2114(1)
1148(2)
1663(2)
3714(7)
4431(8)
2477(8)
3376(7)
3715(9)
1555(7)
1623(9)
1524(9)
1354(10)
1334(9)
1433(9)
520(7)
1542(1)
1983(2)
2380(1)
-556(6)
727(6)
O(1)
O(2)
N(1)
N(2)
N(3)
N(10)
H(10)
C(1)
C(2)
C(3)
C(4)
C(5)
2123(19)
3246(24)
3307(20)
5903(18)
2470(20)
-492(21)
-1225(285)
1673(23)
1109(28)
34(27)
-422(25)
-716(29)
-261(28)
972(26)
1701(20)
1985(20)
1324(23)
130(22)
-43(23)
1128(22)
4681(22)
6115(24)
5952(27)
7161(28)
4742(14)
2112(15)
3462(15)
3069(35)
3888(14)
4623(19)
5329(15)
4178(13)
4711(17)
7415(15)
8383(210)
5874(17)
6436(20)
7382(26)
7710(20)
7109(21)
6539(22)
5696(18)
5408(16)
5834(15)
6217(17)
7159(17)
6821(20)
5990(16)
5205(20)
5128(19)
2980(19)
4248(23)
1456(11)
21(10)
733(5)
2003(5)
-676(6)
2088(5)
1363(7)
1134(8)
1639(8)
2344(8)
2581(8)
2772(6)
2866(7)
3180(8)
3369(7)
3258(7)
2973(7)
3172(6)
3812(6)
4377(7)
4297(8)
3665(8)
3090(8)
-835(7)
-1380(8)
-1645(8)
-1421(7)
-29(6)
538(6)
C(6)
C(7)
C(8)
C(9)
381(8)
-455(11)
-1163(10)
-1033(9)
-204(9)
2421(8)
2194(8)
2870(11)
3724(11)
3935(11)
3274(9)
2805(10)
2768(12)
1896(12)
1086(11)
-619(8)
-634(9)
121(8)
959(7)
1864(9)
278(8)
-353(8)
1953(9)
1086(9)
209(9)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
Cl(1d)
Cl(2d)
Cl(3d)
C(d)
1534(13)
1388(27)
centrosymmetric space groups). The structure amplitudes were obtained
after the usual Lorentz-polarization reductions. The absorption cor-
rection was also performed, via the ψ-scan technique, by using four
reflections: 1, 1, 6; 2, 6, 18; -1, -1, -4; and -2, -6, -16.
The structure was solved by Patterson and Fourier methods and
refined by a full-matrix least-squares method on the basis of 1502
independent reflections with F > 3σ(F). Since not all the H atoms
could be located through the difference Fourier map, the AFIX
instructions of SHELX-7614 were employed to include in the refinement
the remaining hydrogen atoms. The H atom linked to N(10) [H(10)]
was located through the difference Fourier synthesis. The thermal
parameters were refined to 0.1154, fixed at 0.06, Å2, refined to 0.0920,
and fixed at 0.08 Å2 for aromatic, methylene, methyl, and chloroform
(C)H’s, respectively; the thermal parameter for H(10) was fixed at 0.06
Å2. All these thermal parameters resulted to be higher than those of
the C atoms to which the H atoms were connected.
1012(6)
911(5)
189(6)
-697(5)
-1005(5)
-484(7)
-865(6)
-145(6)
301(5)
448(7)
430(10)
140(9)
1455(8)
1654(9)
638(11)
624(10)
2206(10)
1509(12)
7052(14)
6043(10)
6747(27)
997(7)
3322(10)
3432(10)
4235(10)
3315(12)
1438(14)
-458(9)
358(17)
826(7)
1616(7)
1882(9)
2773(6)
4565(11)
4414(7)
5004(12)
a The occupancy factor of Cl and C atoms of the CH2Cl2 molecule
was fixed at 0.5, whereas the C-Cl bond distances were fixed at 1.80
( 0.03 Å via the AFIX instruction of SHELX-76.
The Pt, Cl, O, and N atoms were treated anisotropically, and all the
C and H atoms were treated isotropically. The R and Rw agreement
factors converged to 0.0559 and 0.0561, respectively. The weighted
agreement factor Rw became 0.064 when a set of atomic coordinates,
related to the previous one via the -x, -y, -z transformation, was used.
As a consequence, the second set was rejected. The fractional atomic
coordinates are reported in Table 2.
X-ray Crystallography for 3. Crystals of 3 were grown from CH2-
Cl2 solution. A very thin (ca. 0.15 × 0.20 × 0.03 mm) red plate was
selected for the X-ray analysis and mounted on a glass fiber.
Crystallographic data are listed in Table 1. Unit cell parameters were
computed via least-squares refinement of the values (in the range 2θ
) 10-25°) of 27 carefully centered reflections chosen from different
regions of the reciprocal space. The space group P21/c was selected
on the basis of the systematic extinctions. This finding was in
agreement with the analysis of the normalized structure factors which
indicated a centrosymmetric space group (|E2 - 1| ) 0.911, 0.736 for
non-centrosymmetric space groups, and 0.968 for centrosymmetric
space groups). The structure amplitudes of 9793 reflections ((h, (k,
l, 25 °C, Rint ) 0.035 for 4850 equivalences) were obtained after the
usual Lorentz-polarization reduction. The absorption correction was
performed via the ψ-scan technique by using three reflections: 1, -4,
2; 3, -12, 8; and -1, 3, 2.
The structure was solved through Patterson and Fourier methods
and refined by a full-matrix least-squares method on the basis of 3608
independent reflections with F > 4σ(F). Since only a few H atoms
could be located via the difference Fourier map, the AFIX instructions
of SHELX-7614 were employed to include in the refinement the
remaining H atoms of the acridine ligand.
The C-Cl distances of dichloromethane were fixed at 1.80 ( 0.03
Å, whereas the site occupation factors of the C and Cl atoms of
dichloromethane were fixed at 0.5.
All the non-hydrogen atoms of the complex molecule and the Cl-
ion were refined anisotropically; the H atoms and the C and Cl atoms
of CH2Cl2 were refined isotropically. The fractional atomic coordinates
are reported in Table 3.
Results and Discussion
Coordination of the Acridine. 1-Nitro-9-[(2-(dialkylamino)-
ethyl)amino]acridines (alkyl ) Me, A1; Et, A2) react with
(14) Sheldrick, G. M. SHELX76: Program for Crystal Structure Deter-
mination. University of Cambridge, U.K., 1976.

1-Nitro-9-[(2-aminoethyl)amino]acridines
Inorganic Chemistry, Vol. 35, No. 4, 1996 879
Table 4. 1H Chemical Shifts [δ, Downfield from Si(CH3)4; J(Pt-H) in Hz in Parentheses When Assignable] for Compounds 1, 2, and 3 and
a
Ligands A1 and A2
R
compound
solvent
H(2) H(3) H(4) H(5) H(6)
H(7)
H(8) H(10) C(15)H2
C(16)H2
2.46
CH3
2.31
2.86 (18)
CH2CH3
A1
1
CDCl3
CDCl3
8.02
7.56
7.36
7.62
7.66
7.44
7.91b 7.50c 7.63c
7.81b
3.55
6.72
7.35
7.27
7.35
7.25
6.76
7.49d
8.02 3.75 (33) 3.03 (9)
(CD3)2CO 7.77e 7.80e 7.67e 6.83
7.32 (60)
7.32 (∼40)
7.20 (40)
6.12 (52)
10.80 3.77 (36) 3.13 (10) 2.79 (15)
8.16 3.75 (37) 3.03 (10) 2.82 (14)
CD2Cl2
CD2Cl2
CD2Cl2
7.60
7.49
7.67
8.15
7.66
7.51
7.69
7.54
7.51
8.39
8.65
7.81
6.78
7.30
7.55
1 + Cl-f
3
A2‚2HCl CDCl3
13.35 3.68 (37) 3.00 (9)
14.50 3.66 (14) 3.01 (9)
2.80 (12)
2.22 (18)
8.02b 7.43c 7.71c
8.06b
3.39
2.48
2.56 (CH2)
1.00 (CH3)
3.33 (CH2)
3.07 (CH2)
1.34 (CH3)
2
CDCl3
7.54
7.60
7.49
6.72
7.29
7.50
8.19 3.76 (32) 3.08
a Numbering of atoms in the side chain: C(9)-N(1)-C(15)H2-C(16)H2-N(2)R2 (R ) CH3, A1 or CH2CH3, A2). b The assignment for H(5) and
H(8) can be reversed. c The assignment for H(6) and H(7) can be reversed. d Coupling with platinum obscured by overlapping signals. e Tentative
assignment. f [1] ) 1.8 mM, [Cl-] ) 4 mM.
[PtCl2(DMSO)2] in anhydrous CH2Cl2 to give the compounds
[Pt(A-H)Cl] (A ) A1, 1; A2, 2) in good yield. The reaction
cannot be performed in protic solvents since the alkaline
conditions created by the acridine bases promote a ready
hydrolysis at C(9) with conversion of the acridine into the
corresponding acridone. The chemical formula, [Pt(A-H)Cl],
indicates the presence of only one chloride ion per platinum
atom and loss of a proton by the acridine moiety. 1H NMR
spectra (Table 4) gave clear indication of the coordination to
the metal of both nitrogens of the side chain (numbering of
atoms in the side chain: C(9)-N(1)-C(15)H2-C(16)H2-N(2)-
R2); the two methylene groups between the two nitrogens were
both coupled with the metal (3JPt,H ≈ 30 and 10 Hz for C(15)-
H2 and C(16)H2, respectively). The different coupling constants
indicate that the two nitrogens are trans to ligands of different
trans influence. One of them should be the chloride, and the
other is presumably the carbon atom of a metalated acridine
ring, most likely the C(8) atom which appeared to have lost its
proton. In order to prove such a structure, complex 1 was
reacted with excess triphenylphosphine which is known to
displace coordinated amines but not covalently bound carbon
atoms.15 A new compound incorporating one molecule of PPh3
was obtained (3), but contrary to our expectations, 3 appeared
to keep the terdentate acridine ligand and substitute a phosphine
ligand for the chloride ion. The lack of a coordinated chloride
ligand was suggested by the absence, in the infrared spectrum,
of any bands assignable to a Pt-Cl stretching vibration (νPt-Cl
) 310 cm-1 in 1). Moreover, in the 1H NMR spectrum of the
new phosphine complex, the C(15)H2 methylene group reduced
its coupling with platinum to 14 Hz and showed, in addition, a
4JP,H of 4 Hz.
free ligand was on N(1) is moved on N(10); this gives a singlet
resonance at 8.16 ppm (CD2Cl2 solution).
In compound 2 the resonances of the aromatic protons fall
in the same range as those of compound 1 with similar shifts
with respect to those of the free ligand; moreover, a proton is
localized on N(10) which gives a singlet resonance at 8.19 ppm
(CDCl3 solution). Therefore, also in this case the ligand has
adopted the imino tautomeric form. At the working temperature
(21 °C), the two ethyl substituents at N(2) are equivalent but
the methylene protons exhibit a diastereotopic splitting indicating
that the rotation about the N-ethyl bond is sufficiently slow
for the methylene protons to experience different chemical
environments.
In compound 3 1H NMR data (including a COSY experiment)
also indicate that the acridine is in the imino form with a proton
fixed on N(10). In this compound, however, there is a
considerable spread in the resonance frequencies of the aromatic
protons with respect to compound 1. H(7) and H(6) are shifted
upfield (∆δ ≈ 1.2 and 0.6 ppm, respectively) due to ring current
effects of triphenylphosphine; a similar effect is suffered by the
methyl groups on N(2) (∆δ ≈ 0.6 ppm). H(4) and H(5), on
the contrary, have a considerable downfield shift (∆δ ≈ 1.1
and 0.8 ppm, respectively) with respect to their field position
in 1. The shift becomes dramatic for H(10) which resonates at
14.5 ppm as compared to the 8.16 ppm value of the corre-
sponding proton in 1 (CD2Cl2 solution). The low-field shifts
of H(4) and H(5) and particularly that of H(10) are far too big
to be the consequence of the net positive charge of compound
3. A better explanation can be found in a strong hydrogen bond
involving N(10) and the chloride counterion;17 this point will
be discussed later on in this section.
The Aromatic Moiety. The free ligands A1 and A2 exhibit,
in deuteriochloroform, a 1H NMR pattern for the aromatic
protons which is in accord with the presence of the amino
tautomer. It has already been reported that even 1-nitroacridines
have a preference for amino-type configuration in organic
solvents.7
In compound 1, as a consequence of coordination, the
aromatic protons shift upfield (∆δ ≈ 0.5 and 1.2 ppm for H(2)
and H(5), respectively) in full agreement with the presence of
the imino tautomer.16 The lower multiplicity of the C(15)H2
methylene resonance also indicates that the proton which in the
X-ray Structure of 1. The metal atom is linked to the C(8)
atom of the acridine moiety as well as to the N(1) and N(2)
atoms of the exocyclic chain; a chloride ion completes the
pseudo-square-planar coordination geometry (Figure 1 and Table
5). There are relatively high deviations from the mean plane
defined by the donor atoms [Cl, -0.012(5); C(8), 0.18(2); N(1),
-0.16(1); N(2), 0.12(1); Pt, 0.019(1) Å]. The Pt-N(1) [1.973-
(15) Å] and Pt-N(2) [2.156(15) Å] bond distances differ from
each other by more than 12 times the esd. This difference can
be attributed to two main factors: (i) the different trans influence
of the C(8) and Cl- donors and (ii) the different hybridization
of the nitrogen atoms [sp2 for N(1) and sp3 for N(2)]. The Pt-
(15) Onoue, H.; Mimami, K.; Naka Gawa, K. Bull. Chem. Soc. Jpn. 1970,
43, 3480. Maresca, L.; Natile, G.; Cattalini, L.; Gasparrini, F. J. Chem.
Soc., Dalton Trans. 1975, 1601.
(16) An overall upfield shift which is particularly significant for H(5) and
for the proton ortho to the nitro group [H(2) in this case] is always
observed on going from amino to imino tautomer.
(17) Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 1991,
113, 4917. Maresca, L.; Natile, G.; Fanizzi, F. P.; Stasi, F. J. Am.
Chem. Soc. 1989, 111, 1492.

880 Inorganic Chemistry, Vol. 35, No. 4, 1996
Ceci et al.
the value is very close to the mean value reported for free
acridines in the imino tautomeric configuration.
The steric repulsion between the nitro group and the side
chain in peri positions [O(1)‚‚‚C(15), 2.97(2); O(1)‚‚‚H(15A),
2.31(4), O(1)‚‚‚N(1), 2.97(2); N(3)‚‚‚C(15), 2.88(2); N(3)‚‚‚H-
(15A), 2.37(4), and N(3)‚‚‚N(1), 3.20(2) Å] appears to be
responsible for the displacement of the two groups on opposite
sides with respect to the acridine plane [torsion angles: O(1)-
N(3)-C(1)-C(11), -35(3); N(3)-C(1)-C(11)-C(9), -21(3);
C(1)-C(11)-C(9)-N(1), -20(3), and C(11)-C(9)-N(1)-
C(15), -12(3)°]. As a consequence, the coordination plane
(least-squares plane of the donor atoms) and the acridine plane
(least-squares plane of the 14 atoms of the ring systems) make
an angle of 22.7(3)° and the nitro group is twisted with respect
to the acridine system by 42(1)° [this value is intermediate
between those reported for the free base (60°) and for the
protonated form (30°)].
The formation of a C(8)-N(1) chelate ring also causes a
narrowing of the N(1)-C(9)-C(14) angle [112(2)°] and,
consequently, an increasing of the complementary N(1)-C(9)-
C(11) angle [129(2)°] which contributes to the release of steric
hindrance between the substituents on C(1) and C(9).20,21 The
steric repulsion between the nitro group and the ethylenediamine
side chain in peri positions appears to provide the driving force
to the metalation reaction.
Figure 1. ORTEP drawing of complex 1 with the atom-labeling
scheme. The ellipsoids enclose 50% probability.
X-ray Structure of 3. The coordination geometry of
complex 3 is very similar to that of 1 apart from a triph-
enylphosphine which has taken the place of the chloride ion
(Figure 2 and Table 5). The phosphine ligand causes a
lengthening of the trans Pt-N(1) bond [2.038(9) Å] which,
however, remains significantly shorter than the Pt-N(2) bond
[2.185(9) Å] trans to the carbon donor. The phosphine ligand
also causes a slight lengthening of the two cis coordination
bonds. In 3, with respect to 1, there is a slight contraction of
bonds within the N(1)-N(2) chelating chain and a slight
lengthening of bonds within the N(1)-C(8) chelating chain.
The acridine keeps the imino configuration with a proton on
N(10). The imino configuration is also supported by the
relatively large N(10)-C(12) and N(10)-C(13) bond distances
[average value 1.374(15) Å] and the C(12)-N(10)-C(13) bond
angle [123.9(10)°] (Singh rule).19 The bond distances of the
acridine system are mostly normal within the esd; significant
differences, with respect to compound 1, are a lengthening of
the C(1)-C(11) bond and a slight contraction of the bonds
within the C(1)-C(4) and C(5)-C(8) sequences.
The aromatic moiety is more bent in 3 than in 1, the dihedral
angle between outer rings being 16.1(5)° as compared to the
value of 8.8(7)° found in compound 1; in contrast the dihedral
angle between the least-squares planes of the donor atoms and
of the acridine system is slightly smaller in 3 [18.0(2)°] than in
1 [22.7(3)°]. Finally, the angle formed by the acridine system
and the nitro group [43.7(9)°] is very similar to that found in
the previous compound.
Intermolecular Interactions. Compounds 1 and 3 crystallize
with one and one-half molecule of solvent per molecule of
complex, respectively (chloroform in 1 and dichloromethane
in 3). The solvent of crystallization acts as a hydrogen bond
donor with respect to the nitro group [O(1)‚‚‚H(d) and O(1)‚‚‚C-
(d) distances are 2.33(5) and 3.29(3) Å in 1 and 2.33(5) and
3.29(3) Å in 3, respectively]. The C‚‚‚O contact distances in
the range 3.31-3.57 Å have been reported for C-H‚‚‚O (water)
hydrogen bonding in 46 neutron diffraction crystal structures.21
Figure 2. ORTEP drawing of complex 3 with the atom-labeling
scheme. The ellipsoids enclose 50% probability. The labeling of the
atoms of the PPh3 ligand is omitted for clarity.
C(8) bond distance [1.978(17) Å] falls in the normal range.18
As expected, one of the two five-membered chelates is nearly
planar [torsion angles: Pt-C(8)-C(14)-C(9), -3(2); C(8)-
C(14)-C(9)-N(1), 10(2), and C(14)-C(9)-N(1)-Pt, -12(2)°]
while the second ring exhibits the usual puckering [torsion
angles: Pt-N(1)-C(15)-C(16), 27(2); N(1)-C(15)-C(16)-
N(2), -52(2), and C(15)-C(16)-N(2)-Pt, 50(2)°].
The aromatic moiety is folded along the C(9)-N(10) axis
by 8.8(7)°. This value is, however, smaller than those found
in uncomplexed molecules (range 13-22°).9 The bond dis-
tances within the acridine system are mostly normal, but two
bonds, C(8)-C(14) [1.46(3) Å] and C(11)-C(12) [1.48(3) Å],
appear to be significantly longer. The imino configuration of
the acridine ligand is confirmed by the presence of a proton on
N(10) and by relatively high values of the N(10)-C(12) and
N(10)-C(13) bond lengths [average 1.371(20) Å] and of the
C(12)-N(10)-C(13) angle [122(2)°] (Singh rule).19 Moreover
the C(9)-N(1) bond distance [1.299(25) Å] is quite short, and
(18) Orpen, A. G.; Brammer, L.; Allen, F. H.; Kennard, O.; Watson, D.
G.; Taylor, R. J. Chem. Soc., Dalton Trans. 1989, S1. Ceci, E.; Cini,
R.; Karaulov, A.; Hursthouse, M. B.; Maresca, L.; Natile, G. J. Chem.
Soc., Dalton Trans. 1993, 2491.
(20) For uncoordinated 1-nitroacridines, the N-C(9)-C(11) angle has an
average value of 116° in the free base and a value of 125° in
N-protonated salts (see ref 9).
(19) Singh, C. Acta Crystallogr. 1965, 19, 861.
(21) Steiner, T.; Saenger, W. J. Am. Chem. Soc. 1993, 115, 4540.

1-Nitro-9-[(2-aminoethyl)amino]acridines
Inorganic Chemistry, Vol. 35, No. 4, 1996 881
a
Table 5. Bond Distances (Å) and Angles (deg) for the Atoms of 1‚CHCl3 and 3‚1/2CH2Cl2
1‚CHCl3
3‚1/2CH2Cl2
1‚CHCl3
3‚1/2CH2Cl2
Pt-P
Pt-Cl
Pt-C(8)
Pt-N(1)
Pt-N(2)
2.244(3)
Pt-C(8)-C(7)
Pt-C(8)-C(14)
C(8)-C(14)-C(9)
N(1)-C(9)-C(14)
N(1)-C(9)-C(11)
Pt-N(1)-C(9)
132(1)
109(1)
117(1)
112(2)
129(2)
118(1)
114(1)
128(1)
106(1)
110(2)
103(1)
114(1)
112(2)
110(1)
112(1)
107(2)
133.0(8)
109.7(7)
117.7(9)
114.1(9)
129.0(11)
115.5(8)
116.8(8)
127.7(10)
106.3(10)
110.9(10)
102.9(7)
116.5(8)
109.8(10)
104.6(10)
112.8(8)
109.5(12)
2.311(5)
1.978(17)
1.973(15)
2.156(15)
2.036(10)
2.038(9)
2.185(9)
C(8)-C(14)
C(14)-C(9)
C(9)-N(1)
N(1)-C(15)
C(15)-C(16)
C(16)-N(2)
N(2)-C(17)
N(2)-C(18)
1.458(26)
1.408(26)
1.299(25)
1.548(26)
1.540(28)
1.484(25)
1.442(28)
1.473(29)
1.434(15)
1.455(16)
1.337(15)
1.425(17)
1.505(17)
1.487(16)
1.447(17)
1.498(15)
Pt-N(1)-C(15)
C(9)-N(1)-C(15)
N(1)-C(15)-C(16)
C(15)-C(16)-N(2)
Pt-N(2)-C(16)
Pt-N(2)-C(18)
C(16)-N(2)-C(17)
C(16)-N(2)-C(18)
Pt-N(2)-C(17)
C(1)-C(11)
C(1)-C(2)
C(2)-C(3)
1.392(27)
1.397(29)
1.410(34)
1.385(33)
1.371(28)
1.419(33)
1.379(32)
1.422(32)
1.395(28)
1.441(27)
1.355(26)
1.388(27)
1.475(28)
1.374(28)
1.458(17)
1.352(21)
1.383(21)
1.344(20)
1.386(17)
1.397(16)
1.368(16)
1.388(16)
1.374(15)
1.442(17)
1.350(15)
1.398(15)
1.444(18)
1.398(15)
C(17)-N(2)-C(18)
C(11)-C(1)-C(2)
C(1)-C(2)-C(3)
C(2)-C(3)-C(4)
C(3)-C(4)-C(12)
C(13)-C(5)-C(6)
C(5)-C(6)-C(7)
125(2)
118(2)
119(2)
123(2)
121(2)
120(2)
121(2)
117(1)
119(1)
122(2)
116(2)
130(2)
114(2)
120(2)
119(2)
120(2)
119(2)
120(2)
121(2)
122(2)
120(2)
122.6(14)
119.7(13)
120.8(13)
121.3(13)
117.8(11)
122.3(11)
121.9(11)
116.2(10)
116.8(10)
123.9(10)
117.4(11)
129.2(12)
113.4(12)
119.9(12)
119.5(10)
120.6(12)
120.4(10)
117.8(10)
121.8(11)
121.2(10)
121.0(9)
C(3)-C(4)
C(4)-C(12)
C(13)-C(5)
C(5)-C(6)
C(6)-C(7)
C(7)-C(8)
C(11)-C(9)
C(12)-N(10)
N(10)-C(13)
C(11)-C(12)
C(13)-C(14)
C(6)-C(7)-C(8)
C(7)-C(8)-C(14)
C(11)-C(9)-C(14)
C(12)-N(10)-C(13)
C(12)-C(11)-C(9)
C(1)-C(11)-C(9)
C(1)-C(11)-C(12)
C(4)-C(12)-N(10)
C(11)-C(12)-N(10)
C(11)-C(12)-C(4)
C(5)-C(13)-C(14)
N(10)-C(13)-C(14)
N(10)-C(13)-C(5)
C(13)-C(14)-C(8)
C(13)-C(14)-C(9)
C(1)-N(3)
N(3)-O(1)
N(3)-O(2)
1.484(26)
1.217(24)
1.205(24)
1.452(19)
1.247(15)
1.215(15)
C(d)-Cl(1d)
C(d)-Cl(2d)
C(d)-Cl(3d)
1.722(31)
1.753(32)
1.687(30)
1.801(10)
1.786(10)
Cl-Pt-C(8)
Cl-Pt-N(1)
Cl-Pt-N(2)
P-Pt-C(8)
P-Pt-N(1)
P-Pt-N(2)
C(8)-Pt-N(1)
C(8)-Pt-N(2)
N(1)-Pt-N(2)
98.7(5)
174.3(4)
96.3(5)
C(2)-C(1)-N(3)
C(11)-C(1)-N(3)
C(1)-N(3)-O(2)
C(1)-N(3)-O(1)
O(2)-N(3)-O(1)
114(2)
120(2)
119(2)
115(1)
126(2)
117.8(12)
118.9(12)
118.5(14)
117.1(11)
124.1(14)
94.5(3)
176.2(3)
103.5(3)
82.2(4)
161.1(4)
80.0(4)
81.7(7)
163.4(6)
84.0(7)
a Distances and angles for the PPh3 ligand of 3 are reported in Table S4.
1
Stacking interactions are practically absent even though the
acridine moieties are piled almost perpendicular and parallel to
the [110] plane in 1 and almost parallel to the [101] plane in 3
(Figures 3 and 4 of the supporting information, respectively).
The folding of the acridine ring system associated with
displacements on opposite sides of the acridine plane of the
substituents in 1- and 9-positions (the NO2 group and the metal
coordinated alkyl chain) appears to prevent such a stacking
interaction.
If stacking interactions are absent, intermolecular hydrogen
bonding interactions are extensive in both compounds. In 1
the chloro ligand is hydrogen bonded to N(10) and C(2) atoms
of different molecules [N(10)‚‚‚Cl, 3.421(15); C(2)‚‚‚Cl, 3.61-
(1) Å]. In 3, in which the chloride is a free anion, the N(10)‚‚‚Cl
contact becomes very close [3.14(1) Å].
H-Bonding in Solution. The tendency of H(10) to be
engaged in hydrogen bonding is supported not only by crystal
packing studies but also by NMR data.
In compound 3 the H(10) resonance occurs 6 ppm downfield
with respect to compound 1; a persistence in solution of the
strong N(10)H‚‚‚Cl hydrogen bond, observed in the solid state,
is a likely and attractive explanation.
To prove this hypothesis the H NMR spectrum in CD2Cl2
solution of 1 was monitored in the presence of an equimolar
amount of tetrabutylammonium chloride. The proton resonance
of N(10), initially at 8 ppm, shifted to 12 ppm (downfield from
TMS). The same resonance was shifted further downfield (to
13 ppm) when the amount of chloride in solution was doubled.
Therefore the 6 ppm difference in H(10) chemical shift between
1 and 3 is only due to the availability, in the latter case, of a
chloride counterion in solution which can act as a H-bonding
acceptor. H-bonding with the solvent could also explain the
2.5 ppm downfield shift of H(10) resonance observed when the
NMR spectrum of 1 was taken in acetone instead of chloroform.
In recent years there has been a number of reports concerned
with H-bonding association in different solvents between two
neutral or a neutral and a charged species, some of them
involving a chloride ion.22 In connection with this it is worth
(22) Miura, K.; Tanaka, M.; Fukui, H.; Toyama, H. J. Phys. Chem. 1988,
92, 2390. Barcza, L.; Lenner, L. J. Pharm. Sci. 1988, 77, 622. Dieter,
K. M.; Dymek, C. J., Jr.; Heimer, N. E.; Rovang, J. W.; Wilkes, J. S.
J. Am. Chem. Soc. 1988, 110, 2722. Dymek, C. J., Jr.; Stewart, J. P.
Inorg. Chem. 1989, 28, 1472. Avent, A. G.; Chaloner, P. A.; Day, M.
P.; Seddon, K. R.; Weton, T. J. Chem. Soc., Dalton Trans. 1994, 3505.

882 Inorganic Chemistry, Vol. 35, No. 4, 1996
Ceci et al.
mentioning the stabilization effect by chloride ions in certain
organic-protonated bases. For instance, the diprotonated tet-
rapyridylpyridazine assumes a distorted structure with Cl- as
counterions while substitution of tetraphenylborate for chloride
ion causes collapsing to a quasi planar structure with intramo-
lecular N-H‚‚‚N hydrogen bonds.23 Similarly, chloride coun-
terions stabilize the diprotonated form of 5,10,15,20-tetraphe-
nylporphirine Via association into tight contact ion pairs.24 The
N-H‚‚‚Cl hydrogen interaction is also thought to be crucial in
stabilizing the bis(dithiooxamide)platinum(II) dication.25
interaction, however, remains rather large and promotes a 20°
rotation of the coordination plane with respect to the acridine
plane.
Coordination appears to stabilize the imino tautomer with a
proton on N(10). It is to be noted that also the unsubstituted
9-aminoacridine, when coordinated to platinum through its
exocyclic nitrogen atom, was found to adopt the imino tauto-
meric form.27 If the imino tautomerism of 1-nitroacridines has
some relevance to their antitumor activity, the coordination of
a platinum atom to the 9-(2-aminoethyl)amino chain would be
beneficial.
Conclusions
The H(10) proton has a great tendency to be engaged in
hydrogen bonding as shown by X-ray and solution studies. The
H-bond formation can cause a downfield shift of the H-
resonance as large as 6 ppm.
The severe steric interactions between the 1-nitro and the
9-alkylamino groups in the peri positions of the acridine ring
system, which are responsible for the imino-type configuration
and folding about the C(9)-N(10) vector of the 1-nitro-9-[(2-
aminoethyl)amino]acridines and possibly their antitumor activ-
ity, are also responsible for their unexpected reactivity toward
platinum.
Finally, the toxicity of these complexes in which the platinum
moiety is not tethered but is incorporated in the intercalator
moiety appears to be comparable to that of the free acridines.
Coordination to platinum of the 9-(2-aminoethyl)amino chain
is accompanied by a simultaneous metalation reaction which
prevents the obtainment of the simple N-coordinated product.
A metalation reaction in such bland conditions has not been
observed with strictly related ligands which also can give
tricoordinate (N,N,C) species.26 The steric repulsion between
the 1-nitro and the 9-(2-aminoethyl)amino groups, enhanced by
the imino-type configuration of the acridine which forces the
sp2-hybridized N(1) moiety to be coplanar with the acridine ring
system, brings the platinum atom very close to C(8)H, thus
providing a driving force to metalation. Moreover in the
metalated species, because of the constraints within the chelate
ring, the N(1)-C(9)-C(14) angle is narrowed (112°), and
consequently the complementary N(1)-C(9)-C(11) angle
becomes larger (129°) and contributes to some release of steric
hindrance between the substituents in C(1) and C(9). The steric
Acknowledgment. This work was supported by the Minis-
tero della Universita` e della Ricerca Scientifica e Tecnologica
(MURST, contribution 40%), the Consiglio Nazionale delle
Ricerche (CNR), the European Community (EC, Contract C11-
CT92-0016 and COST Chemistry project D1/02/92), and the
University of Siena (contribution 60%). The data collections
were carried out by Mr. F. Berrettini at CIABS, University of
Siena.
Supporting Information Available: Full table of crystallographic
data (Table S1), full list of atomic coordinates [Tables S2 (1) and S3
(3)], bond distances and angles for the phosphine ligand in 3 (Table
S4), listing of thermal parameters [Tables S5 (1) and S6 (3)], and crystal
packing diagrams [Figures 3 (1) and 4 (3)] (10 pages). Ordering
information is given on any current masthead page.
(23) Staab, H. A.; Saupe, T. Angew. Chem., Int. Ed. Engl. 1988, 27, 865.
(24) Karaman, R.; Bruice, T. C. Inorg. Chem. 1992, 31, 289.
(25) Rosace, G.; Bruno, G.; Mansu` Scolaro, L.; Nicolo`, F.; Sergi, S.; Lanza,
S. Inorg. Chim. Acta 1993, 208, 59.
(26) Minghetti, G.; Cinellu, M. A.; Chelucci, G.; Gladiali, S.; De Martin,
F.; Manassero, M. J. Organomet. Chem. 1986, 307, 107.
IC950804T
(27) Sundquist, W. J.; Bancroft, D. P.; Lippard, S. J. J. Am. Chem. Soc.
1990, 112, 1590.