Synthesis of bis[palladium(II)] and bis[platinum(II)] complexes containing chiral, linear quadridentate ligands with a P2N2 donor set

Article abstract of DOI:10.1039/b106861j

A number of bis[palladium(II)] and bis[platinum(II)] complexes of the type [(MCl₂)₂(μ-quadridentate)] [where M = Pd(II) or Pt(II)] and [(PtClMe)₂(μ-quadridentate)] have been prepared containing the linear quadridentate NPP

Full text of DOI:10.1039/b106861j

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Synthesis of bis[palladium(II)] and bis[platinum(II)] complexes
containing chiral, linear quadridentate ligands with a P2N2 donor
set†
Justine Bennett,a A. David Rae,b Geoffrey Salem,*a Natalie C. Ward,a Paul Waring,a
Kerri Wellsa and Anthony C. Willisb
a Chemistry Department, The Faculties, Australian National University, Canberra,
A. C. T. 0200, Australia. E-mail: Geoff.Salem@anu.edu.au
b Research School of Chemistry, Australian National University, Canberra, A. C. T. 0200,
Australia
Received 30th July 2001, Accepted 29th October 2001
First published as an Advance Article on the web 10th December 2001
A number of bis[palladium()] and bis[platinum()] complexes of the type [(MCl2)2(µ-quadridentate)] [where M =
Pd() or Pt()] and [(PtClMe)2(µ-quadridentate)] have been prepared containing the linear quadridentate NPPN
ligands 1,3-bis[(2-aminophenyl)phenylphosphino]propane, 1; 1,4-bis[(2-aminophenyl)phenylphosphino]butane, 2;
1,5-bis[(2-aminophenyl)phenylphosphino]pentane, 3 [Pd() only]; 1,6-bis[(2-aminophenyl)phenylphosphino]hexane,
4; and 1,3-bis[(2-aminoethyl)phenylphosphino]propane, 5; and the related PNNP ligands 1,3-bis[(2-diphenylphos-
phinophenyl)amino]propane, 6; and 1,2-bis[(2-diphenylphosphinophenyl)amino]ethane, 7 [Pt() only]. Separation
of the racemic and meso diastereomers of the linear quadridentate NPPN ligands and the resolution of (RP*,RP*)-1
have been achieved via separation by fractional crystallisation of a pair of bis[palladium()] complexes containing the
respective ligand and orthometallated N,N-dimethylbenzylamine or (S)-dimethyl(1-phenylethyl)amine, respectively.
The structure of the bis[palladium()] complex containing (RP,RP)-1 has been confirmed by X-ray analysis and
shown to have the configuration (SP,SP,S,S). Subsequent reaction of stereoisomerically pure [{Pd(2-C6H4CH2-
NMe2)}2(µ-L)](PF6)2 with HCl gave the corresponding complexes [(PdCl2)2(µ-L)] [where L = (RP*,RP*)-1–5, (RP,RP)-
or (SP,SP)-1, (RP*,SP*)-1, -2 or -5]. The analogous complex [(PdCl2)2(µ-6)] has been prepared in a similar manner.
Bis[platinum()] complexes of the type [(PtClMe)2(µ-L)] [where L = (RP*,RP*)-1, -2 or -4; (RP,RP)-, (SP,SP)- or
(RP*,SP*)-1; 6 or 7] have been prepared by reaction of L with [PtCl(Me)(cod)] (cod = cyclocta-1,5-diene). Further
treatment with HCl gave the analogous complexes [(PtCl2)2(µ-L)] [where L = (RP*,RP*)-1, -2, -4 or -5; (RP*,SP*)-1
or -5; or 6]. The dinuclear compounds and, in particular, the bis[platinum()] complexes, are seen as potential
anticancer agents. Preliminary in vitro biological studies have shown them to be active against the murine P388
leukaemia cell-line with cytotoxicities of certain of these complexes being comparable to that of cisplatin.
Several linear quadridentate P2N2 ligands containing stereo-
genic phosphorus donor atoms and terminal primary amine
groups have been reported in the literature.1–4 The ligands
typically contain 2–4 methylene linkages between the phos-
phorus centres and a 1,2-phenylene or 2–3 methylene units
linking the phosphorus and nitrogen atoms. Quadridentate
ligands of this type exist in racemic and meso diastereomeric
forms, however, only in the case of 1,3-bis(2-aminophenyl)-
phenylphosphino]propane, 1, has their separation been
reported, by complexation to platinum().4 Two mononuclear
cations [PtCl{(RP*,RP*)-1}]ϩ and [Pt{(RP*,SP*)-1}]2ϩ were
identified in which the two diastereomeric forms of the ligand
were coordinated in a tridentate and tetradentate fashion,
respectively. The structure of the former was confirmed by
X-ray analysis and clearly established that only one of the
terminal primary amine groups of (RP*,RP*)-1 was coordinated
to the metal centre. A similar mode of coordination was
observed in the dinuclear rhodium() complex [{Rh(CO)}2(µ-
{(RP*,RP*)-1})2].4 Here a mono-deprotonated PN bidentate
group from one quadridentate ligand and a phosphorus atom
from the other were coordinated to the same metal centre.
In this paper we report on an alternative method of
separation of (RP*,RP*)- and (RP*,SP*)-1 and the resolution
of the former, in both cases by the fractional crystallisation of
bis[palladium()] complexes containing the ligand and ortho-
metallated N,N-dimethylbenzylamine or (S)-dimethyl(1-
phenylethyl)amine, respectively. The separation of the
(RP*,RP*) and (RP*,SP*) forms of several related linear quadri-
dentate P2N2 ligands, viz. 1,4-bis[(2-aminophenyl)phenylphos-
phino]butane, 2, 1,5-bis(2-aminophenyl)phenylphosphino]-
pentane, 3, 1,6-bis(2-aminophenyl)phenylphosphino]hexane, 4,
and 1,3-bis[(2-aminoethyl)phenylphosphino]propane, 5,1 using
a similar methodology is also described. Subsequent reaction of
the complexes with HCl provides a route to the related bis-
[dichloropalladium()] compounds [(PdCl2)2(µ-quadridentate)].
The preparation of the analogous bis[dichloropalladium()]
complex containing 1,3-bis[(2-diphenylphosphinophenyl)-
amino]propane, 6,5 is also described. Several examples of
dinuclear palladium() complexes containing linear quad-
ridentate P2N2 ligands with terminal diphenylphosphino or
oxazolyl groups have been reported in the literature.6
A preparative route to the analogous bis[dichloroplatinum-
()] complexes [(PtCl2)2(µ-quadridentate)] is also described via
the reaction of appropriate forms of the quadridentate ligands
with (1,5-cycloctadiene)chloromethylplatinum(), to give
[(PtClMe)2(µ-quadridentate)], followed by treatment with HCl.
The synthesis of the related complexes [(PtClMe)2(µ-L)] [where
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/dt/b1/b106861j/
234
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This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b106861j

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L = 6 or 1,2-bis[(2-diphenylphosphinophenyl)amino]ethane,7 7]
and [(PtCl2)2(µ-6)] is also described. We have previously used a
similar approach to prepare mono(bidentate) complexes of
platinum() containing bidentate ligands with a stereogenic
phosphorus donor atom and a primary amine group.8 More-
over, these complexes were shown to exhibit antiproliferative
activity against the mouse tumour model P815 in vitro with
cytotoxicities of certain of the complexes being comparable to
that of cisplatin, cis-[PtCl2(NH3)2]. Sadler et al. have recently
reported on the synthesis of a number of related mononuclear
platinum() complexes containing achiral bidentate ligands
with phosphorus and nitrogen donor atoms that are seen as
potential dual-mode anticancer agents.9 The dinuclear com-
plexes [(MCl2)2(µ-quadridentate)] [where M = Pd() or Pt()]
and [(PtClMe)2(µ-quadridentate)] are similarly seen as potential
anticancer agents. Accordingly, some preliminary biological
results concerning the in vitro cytotoxicities of certain of these
complexes against the mouse tumour model P388 are also
reported. The achiral multinuclear platinum-based compound
BBR3464,
[Pt3Cl2(NH3)5{µ-H2N(CH2)6NH2}](NO3)4,10
is
currently undergoing extensive clinical trials.
Fig. 1 Stereochemical representation of the linear quadridentate
ligands (RP*,RP*)-5, (RP*,SP*)-5, 6 and 7.
Results and discussion
Synthesis of quadridentate ligands
Separation of (RP*,RP*)- and (RP*,SP*)-L
The linear quadridentate NPPN ligands 1,4 2, 3, and 4 were
synthesised by reaction of secondary phosphine ( )-(2-amino-
phenyl)phenylphosphine11 with sodium in thf followed by the
addition of one-half equivalent of the appropriate dibromo-
alkane (Scheme 1). All four ligands were isolated as air-stable
Separation of the (RP*,RP*) and (RP*,SP*) forms of the five
linear quadridentate NPPN ligands was achieved by fractional
crystallisation of bis[palladium()] complexes containing the
respective ligand and orthometallated N,N-dimethylbenzyl-
amine. For example, reaction of (RP*,RP*)-/(RP*,SP*)-1–4 with
the chloro-bridged dimer di-µ-chloro-bis[2-(dimethylamino-
methyl)phenyl-C1,N]dipalladium(), 8,12 in methanol followed
by the addition of aqueous ammonium hexafluorophosphate
gave a mixture of two diastereomeric salts, viz. [{Pd(2-C6H4-
CH2NMe2)}2(µ-L)](PF6)2 [where L = (RP*,RP*)- or (RP*,SP*)-
1–4], that in each case was readily separated by fractional
crystallisation from hot methanol (Scheme 2). The related
diastereomeric salts [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,RP*)-
5}](PF6)2 and [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,SP*)-5}](PF6)2
were isolated in a similar manner.
Typically an excess of aqueous ammonium hexafluorophos-
phate was used in the above reactions, however, in the case of
ligands 1 and 2, but not 3–5, it was found to be beneficial
to carry out the addition in two steps. The addition of one
equivalent of aqueous ammonium hexafluorophosphate to a
methanolic solution of 1 and 8 gave a complex containing
only (RP*,RP*)-1. Similar treatment of a methanolic solution
of 2 and 8 gave a product enriched in (RP*,RP*)-2. Further
addition of aqueous ammonium hexafluorophosphate to each
of these solutions gave a complex enriched in the (RP*,SP*)
diastereomer of the respective ligand. In each case recrystallisa-
tion from hot methanol gave the respective diastereomerically
pure complex.
Scheme 1 (i) Na, thf; (ii) 0.5 BrCH2(CH2)nCH2Br (where n = 1–4).
The diastereomerically pure complexes [{Pd(2-C6H4CH2N-
Me2)}2(µ-L)](PF6)2 [where L = (RP*,RP*)-1–5, (RP*,SP*)-1, -2
or -5] have been isolated in the current work. Analogous
dipalladium() complexes enriched in (RP*,SP*)-3 or -4
have also been obtained, however, they could not be further
separated by fractional crystallisation. The least soluble
diastereomeric hexafluorophosphate salt in each case has been
assigned the (RP*,RP*) configuration based on X-ray analyses
of two related complexes containing (RP,RP)-1 and (RP*,SP*)-
5, viz. [(Pd{(S)-2-C6H4CHMeNMe2})2{µ-(SP,SP)-1}](PF6)2 ‡
white crystalline solids containing both racemic and meso
diastereomers upon recrystallisation from hot methanol. In the
case of 1 partial but not complete separation of the (RP*,RP*)
and (RP*,SP*) diastereomers was achieved by this process. The
related linear quadridentate NPPN ligand 5 was prepared in
a similar manner by reaction of secondary phosphine ( )-(2-
aminoethyl)phenylphosphine with sodium in thf followed by
the addition of one-half equivalent of 1,3-dibromopropane.1
The linear quadridentate PNNP ligands 6 and 7 were prepared
by a standard metal template approach that involved reaction
of the complex cis-[Ni(2-HNC6H4PPh2)2] with one-half equiva-
lent of 1,3-bis(tolyl-4-sulfonyloxy)propane or 1,2-bis(tolyl-
4-sulfonyloxy)ethane, respectively, in toluene.5,7 The two
diastereomeric forms of 5, (RP*,RP*)- and (RP*,SP*)-5, and
the PNNP ligands 6 and 7 are depicted in Fig. 1.
and
[(Pd{(R)-2-C6H4CHMeNMe2})2{µ-(RP*,SP*)-5}](PF6)2,
respectively (vide infra). The related dinuclear palladium()
complex [{Pd(2-C6H4CH2NMe2)}2(µ-6)](PF6)2 was similarly
prepared via reaction of 8 with the linear quadridentate PNNP
ligand 6 in methanol followed by the addition of aqueous
ammonium hexafluorophosphate.
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Scheme 2 (i) MeOH; (ii) NH4PF6 in H2O.
Treatment of the diastereomerically pure salts [{Pd(2-
C6H4CH2NMe2)}2(µ-L)](PF6)2 [where L = (RP*,RP*)-1–4] with
concentrated hydrochloric acid in methanol gave the corre-
sponding bis[dichloropalladium()] complexes [(PdCl2)2(µ-L)]
(Scheme 3). The related dinuclear dichloropalladium()
complexes [(PdCl2)2{µ-(RP*,RP*)-5}], [(PdCl2)2{µ-(RP*,SP*)-L}]
(where L = 1, 2 or 5) and [(PdCl2)2(µ-6)] were prepared in a
similar manner. The diastereomerically pure forms of certain
of these linear quadridentate NPPN ligands have also been iso-
lated via reaction of the appropriate bis[dichloropalladium()]
complex with aqueous potassium cyanide, namely (RP*,RP*)-1–
5 and (RP*,SP*)-1 and -5.§
Scheme 3 (i) MeOH, conc. HCl; (ii) MeOH, KCN, CH2Cl2, H2O.
amino)ethyl]phenyl-C1,N}dipalladium(), (S)-9,15 in methanol
followed by the addition of an excess of aqueous ammonium
hexafluorophosphate gave a 1 : 1 diastereomeric mixture of the
bis[palladium()] complexes (RP,RP,S,S)- and (SP,SP,S,S)-10
(Scheme 4). Fractional crystallisation of the diastereomeric
mixture from acetone by the dropwise addition of diethyl
ether gave pure (SP,SP,S,S)-10, α ϩ128Њ (589 nm, acetone).
The mother liquor was taken to dryness and the residue
twice recrystallised from acetone–diethyl ether to give pure
(RP,RP,S,S)-10, α Ϫ19Њ (589 nm, acetone). Subsequent treat-
ment of the diastereomerically pure complex (SP,SP,S,S)-10
with concentrated hydrochloric acid in hot methanol gave
the corresponding optically active bis[dichloropalladium()]
complex [(PdCl2)2(µ-{(SP,SP)-1})], α ϩ72Њ (589 nm, dichloro-
methane) (Scheme 5). The enantiomeric dinuclear dichloro-
palladium() complex [(PdCl2)2(µ-{(RP,RP)-1})] was isolated in
a similar manner, α Ϫ72Њ (589 nm, dichloromethane). Further
reaction of [(PdCl2)2(µ-{(RP,RP)-1})] and [(PdCl2)2(µ-{(SP,SP)-
1})] with aqueous potassium cyanide gave the enantiomerically
pure linear quadridentate NPPN ligands (SP,SP)- and (RP,RP)-
1, respectively, α 65Њ (589 nm, dichloromethane).
Resolution of (RP*,RP*)-1
The resolution of (RP*,RP*)-1 has been achieved via the
separation by fractional crystallisation of a pair of internally
diastereomeric dinuclear palladium() complexes containing
the racemic ligand and optically active, orthometallated (S)-
dimethyl(1-phenylethyl)amine. Reaction of (RP*,RP*)-1 with
the chloro-bridged dimer di-µ-chloro-bis{(S)-2-[1-(dimethyl-
‡ The apparent inversion of configuration at phosphorus upon
coordination of (RP,RP)-1 to the palladium() centres is consistent with
the specification of Cahn et al. for absolute configurations.13
§ The relative configuration of (RP*,SP*)-5 was determined via a crystal
structure determination of the complex [(Pd{(R)-2-C6H4CH-
MeNMe2})2{µ-(RP*,SP*)-5}](PF6)2.14 The latter was prepared by
reaction of the diastereomerically pure quadridentate ligand with the
chloro-bridged dimer (R)-9 in methanol followed by the addition of
aqueous NH4PF6.
236
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Scheme 4 (i) MeOH; (ii) NH4PF6 in H2O.
Scheme 6 (i) [PtCl(Me)(cod)], thf; (ii) thf, conc. HCl.
a similar manner. The optically active diplatinum() complex
[(PtClMe)2{µ-(SP,SP)-1}] was similarly prepared via reaction
of (RP,RP)-1 with two equivalents of [PtCl(Me)(cod)] in thf
(Scheme 5), α ϩ93Њ (589 nm, dichloromethane). The enantio-
meric bis[chloro(methyl)platinum()] complex [(PtClMe)2{µ-
(RP,RP)-1}] was prepared in a likewise manner, α Ϫ93Њ (589 nm,
dichloromethane).
Crystal structure determination of (SP,SP,S,S)-10
The absolute configuration of (RP,RP)-1 was assigned by a
crystal structure determination of (SP,SP,S,S)-10. The stereo-
chemistry of the cation is depicted in Fig. 2. Selected bond
lengths and angles are given in Table 1. The structural data
clearly show the presence of a dinuclear palladium() cation
in which the optically active linear quadridentate ligand is
coordinated to both metal centres via a stereogenic phosphorus
atom and a terminal primary amine group. An optically active,
orthometallated dimethyl(1-phenylethyl)amine completes the
coordination sphere of each metal centre. The absolute con-
figurations of the two phosphorus stereocentres and the stereo-
genic carbon atoms of the orthometallated amines were all
S. Furthermore, the pair of nitrogen atoms coordinated to each
of the palladium() centres had adopted a cis geometry in each
case. A similar arrangement of donor atoms was observed
in related mononuclear palladium() complexes containing
an optically active, orthometallated amine and an asymmetric
bidentate ligand with both phosphorus and nitrogen donor
atoms, viz. (RP)-(2-aminophenyl)(2-chlorophenyl)methylphos-
Scheme 5 (i) MeOH, conc. HCl; (ii) MeOH, KCN, CH2Cl2, H2O; (iii)
[PtCl(Me)(cod)], thf.
Preparation of dinuclear platinum(II) complexes
Dinuclear platinum() complexes of the type [(PtClMe)2{µ-
(RP*,RP*)-L}] (where L = 1, 2 or 4) have been prepared via
reaction of the respective racemic quadridentate ligand with
two equivalents of [PtCl(Me)(cod)] (where cod = cycloocta-
1,5-diene)16 in thf (Scheme 6). Subsequent treatment of
[(PtClMe)2{µ-(RP*,RP*)-L}] with concentrated hydrochloric
acid in methanol gave the corresponding bis[dichloroplatinum-
()] complexes [(PtCl2)2{µ-(RP*,RP*)-L}] [where L = 1, 2 or 4].
The related dinuclear platinum() complexes [(PtClMe)2(µ-L)]
[where L = (RP*,SP*)-1, 6 or 7] and [(PtCl2)2(µ-L)] [where L =
(RP*,SP*)-1, (RP*,RP*)- or (RP*,SP*)-5 or 6] were all prepared in
phine
and
(RP)-methylphenyl(8-quinolyl)phosphine.15,17
Furthermore, the bond lengths and angles around the two
palladium() centres in (SP,SP,S,S)-10 are very similar and
comparable to those in the aforementioned mononuclear
complexes.
The linear tetra(tertiary phosphine) (RP*,RP*)-1,2-bis[(2-di-
phenylphosphinoethyl)phenylphosphino]ethane has previously
been resolved by the method of metal complexation and
similarly shown to form a pair of diastereomeric dinuclear
palladium() complexes upon reaction with (R)-9.18 There are
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(RP*,SP*)-1, -2 or -5], each contained a singlet phosphorus
resonance consistent with the presence of a single diastereomer.
A singlet phosphorus resonance was similarly observed for
[{Pd(2-C6H4CH2NMe2)}2(µ-6)](PF6)2. Furthermore, the 1H
NMR spectra of the complexes containing the linear quadri-
dentate NPPN ligands 1–5 are consistent with the solid state
structure of (SP,SP,S,S)-10. For example, coupling of the
phosphorus stereocentres to the trans disposed NMe groups
and the methine protons of (SP,SP,S,S)- and (RP,RP,S,S)-10,
or the benzylic protons of [{Pd(2-C6H4CH2NMe2)}2(µ-L)]-
(PF6)2 [where L = (RP*,RP*)-1–5 or (RP*,SP*)-1, -2 or -5], was
1
evident in the respective H NMR spectra. A similar finding
has previously been reported for mononuclear palladium()
complexes containing an orthometallated amine and the
enantiomers of ( )-(2-aminoethyl)methylphenylphosphine,19
( )-(2-aminophenyl)methylphenylphosphine,11 ( )-(2-amino-
phenyl)(2-chlorophenyl)methylphosphine17 and ( )-methyl-
phenyl(8-quinolyl)phosphine.15 Similar coupling of the phos-
phorus donor atoms to the trans disposed NMe groups and the
benzylic protons of the orthometallated amine was evident
1
in the H NMR spectrum of [{Pd(2-C6H4CH2NMe2)}2(µ-6)]-
1
(PF6)2. Selected H and 31P-{1H} NMR data for the optically
active dinuclear palladium() complexes (SP,SP,S,S)- and
(RP,RP,S,S)-10, the related diastereomerically pure complexes
[{Pd(2-C6H4CH2NMe2)}2(µ-L)](PF6)2 [where L = (RP*,RP*)-1–5
or (RP*,SP*)-1, -2 or -5] and [{Pd(2-C6H4CH2NMe2)}2(µ-6)]-
(PF6)2 are given in Table 2.
The 31P-{1H} NMR spectra of the related dinuclear com-
plexes [(PdCl2)2(µ-L)] [where L = (RP,RP)-, (SP,SP)-, (RP*,RP*)-
or (RP*,SP*)-1; (RP*,RP*)- or (RP*,SP*)-2; (RP*,RP*)-3; or
(RP*,RP*)-4], [(PtClMe)2(µ-L)] [where L = (RP,RP)-, (SP,SP)-,
(RP*,RP*)- or (RP*,SP*)-1; (RP*,RP*)-2 or -4; or 7] and
[(PtCl2)2(µ-L)] [where L = (RP*,RP*)-1, (RP*,SP*)-1, (RP*,RP*)-2
or -4] each contained a singlet 31P resonance consistent with the
presence of a single diastereomeric complex. Two singlet 31P
resonances were observed for the complexes [(PdCl2)2(µ-6)],
[(PtClMe)2(µ-6)] and [(PtCl2)2(µ-6)] in their respective 31P-{1H}
NMR spectra consistent with the presence of two diastereo-
mers that presumably arise as a result of coordination of the
two stereogenic secondary amine groups of the linear quadri-
dentate PNNP ligand 6. Diastereoisomerism arising from the
presence of coordinated chiral secondary amines in kinetically
inert transition metal complexes has been well documented.20–22
The 31P resonances of the dinuclear platinum() complexes
were also flanked by satellites due to 195Pt–31P coupling, the
1JPtP values of which were consistent with the phosphorus
donor atoms being trans to chloro groups.8,23
Fig. 2 Molecular structure of the cation (SP,SP,S,S)-10.
Table 1 Selected non-hydrogen interatomic distances (Å) and inter-
atomic angles (Њ) for (SP,SP,S,S)-10
Pd(1)–P(1)
Pd(1)–N(1)
Pd(1)–N(2)
Pd(1)–C(15)
2.206(2) Pd(1)Ј–P(1)Ј
2.159(6) Pd(1)Ј–N(1)Ј
2.144(6) Pd(1)Ј–N(2)Ј
2.007(7) Pd(1)Ј–C(15)Ј
2.207(2)
2.159(6)
2.144(6)
2.006(8)
P(1)–Pd(1)–N(1)
P(1)–Pd(1)–N(2)
P(1)–Pd(1)–C(15)
N(1)–Pd(1)–C(15)
N(1)–Pd(1)–N(2)
C(15)–Pd(1)–N(2)
Pd(1)–P(1)–C(1)
Pd(1)–P(1)–C(9)
Pd(1)–P(1)–C(8)
Pd(1)–N(1)–C(3)
Pd(1)–C(15)–C(20) 112.6(6)
Pd(1)–C(15)–C(16) 128.8(6)
Pd(1)–N(2)–C(21)
Pd(1)–N(2)–C(24)
Pd(1)–N(2)–C(23)
85.5(2)
177.7(2)
97.2(2)
176.8(3)
95.4(3)
P(1)Ј–Pd(1)Ј–N(1)Ј
85.2(2)
174.0(2)
97.4(2)
176.5(3)
95.9(3)
P(1)Ј–Pd(1)Ј–N(2)Ј
P(1)Ј–Pd(1)Ј–C(15)Ј
N(1)Ј–Pd(1)Ј–C(15)Ј
N(1)Ј–Pd(1)Ј–N(2)Ј
C(15)Ј–Pd(1)Ј–N(2)Ј
Pd(1)Ј–P(1)Ј–C(1)Ј
Pd(1)Ј–P(1)Ј–C(9)Ј
Pd(1)Ј–P(1)Ј–C(8)Ј
Pd(1)Ј–N(1)Ј–C(3)Ј
Pd(1)Ј–C(15)Ј–C(20)Ј
Pd(1)Ј–C(15)Ј–C(16)Ј
Pd(1)Ј–N(2)Ј–C(21)Ј
Pd(1)Ј–N(2)Ј–C(24)Ј
Pd(1)Ј–N(2)Ј–C(23)Ј
82.0(3)
81.9(3)
116.6(4)
117.9(2)
102.9(3)
115.6(5)
114.2(4)
121.5(2)
103.2(3)
115.8(5)
112.3(6)
129.2(6)
106.0(5)
104.8(6)
116.2(6)
Two broad singlet 31P resonances flanked by satellites were
similarly observed for the bis[dichloroplatinum()] complexes
[(PtCl2)2(µ-L)] [where L = (RP*,RP*)- or (RP*,SP*)-5] in their
respective 31P-{1H} NMR spectra, however, the chemical shifts
of the signals and the associated 195Pt–31P coupling constants
in each case were significantly different. Similar data has
previously been reported for the monuclear cation [PtCl-
{(RP*,RP*)-1}]ϩ where only one nitrogen atom of the quadri-
dentate ligand was coordinated to the metal centre.4 The
suggestion is that the dinuclear complexes [(PtCl2)2(µ-L)] [where
L = (RP*,RP*)- or (RP*,SP*)-5] rearrange in dmso to form
mononuclear species of the type [PtCl(L)]ϩ in which the ligand
is similarly coordinated in a tridentate fashion via the two
phosphorus centres and one nitrogen atom. The upfield signal
in each case is assigned to the phosphorus centre trans to the
chloro group and the other to the phosphorus atom trans to
106.9(5)
106.1(6)
116.3(6)
many similarities between the structures of the diastereomeric
complex containing the (SP,SP) form of the tetra(tertiary
phosphine) and that of (SP,SP,S,S)-10. For example, in both
cases the stereogenic phosphorus centres were trans to the
dimethylamino group of the orthometallated amine and the
methyl substituents of the carbon stereocentres had adopted an
axial disposition. The optical antipodes of the tetra(tertiary
phosphine) were subsequently shown to spontaneously self-
assemble into homochiral double-stranded bimetallic helicates
on complexation to gold() and silver().18
1
the primary amine. The respective JPtP values are consistent
with this assignment. The analogous bis[dichloropalladium()]
complexes [(PdCl2)2(µ-L)] [where L = (RP*,RP*)- or (RP*,SP*)-5]
were similarly unstable in dmso, the respective 31P-{1H} NMR
spectra contained four singlet resonances. The data here are
inconsistent with the presence of a single species in solution.
Selected 1H and 31P-{1H} NMR data for the quadridentate
NMR spectra
The 31P-{1H} NMR spectra of the optically active dinuclear
palladium() complexes (SP,SP,S,S)- and (RP,RP,S,S)-10,
and of the related diastereomerically pure complexes [{Pd-
(2-C6H4CH2NMe2)}2(µ-L)](PF6)2 [where L = (RP*,RP*)-1–5 or
238
J. Chem. Soc., Dalton Trans., 2002, 234–243

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Table 2 Selected 1H and 31P-{1H} NMR data for the dinuclear palladium() complexes [{Pd(2-C6H4CH2NMe2)}2(µ-L)](PF6)2 [where L = (RP*,RP*)-
1–5, (RP*,SP*)-1–5 or 6], (RP,RP,S,S)- and (SP,SP,S,S)-10 in (CD3)2CO
1H
31P-{1H}
L
δ(P)
δ(CCH2C)
δ(PCH2)
δ(NMe2)
δ(NCH2)
δ(CH2NMe2)a
(RP*,RP*)-1
(RP*,SP*)-1
(RP*,RP*)-2
(RP*,SP*)-2
(RP*,RP*)-3
(RP*,RP*)-4
(RP*,RP*)-5
(RP*,SP*)-5
6
39.8s
37.1s
39.9s
38.2s
39.5s
39.0s
52.6s
51.8s
39.4s
1.93m
2.77m
2.88m
2.77bs, 2.93d
2.93d, 3.00bs
2.93bs, 3.04bs
2.91bs, 3.01bs
2.95bs, 3.03d
2.94bs, 3.03bs
2.87bs, 2.95bs
2.84bs, 2.89bs
2.91bs
—
—
—
—
—
—
3.60, 4.15
3.78, 4.31
3.78, 4.48
3.74, 4.91
3.99, 4.25
3.81, 4.41
3.60, 4.61
3.69, 4.35
4.09bs
1.75m, 2.22m
1.47m, 1.97m
1.73m, 1.87m
1.35m, 1.55m
1.30m, 1.62m
2.15m
2.41m, 2.78m
2.42m, 2.68m
2.45m, 2.72m
2.51m, 2.81m
2.25m, 2.65m
2.34m, 2.61m
—
3.10m, 3.25m
3.05m, 3.15m
3.58m
2.14m
1.98m
1H
31P-{1H}
Compound
δ(P)
δ(CMe)
δ(CCH2C)
δ(PCH2)
δ(NMe2)
δ(CH)
(RP,RP,S,S)-10
(SP,SP,S,S)-10
36.8s
37.5s
1.46d
1.60d
1.83m
1.93m
2.73m, 3.12m
2.81m, 3.19m
2.88d, 2.90bs
2.72bs, 2.90bs
3.82dq
3.82dq
a AB part of an ABX spin system unless otherwise indicated.
ligands 1–5 and the dinuclear complexes [(MCl2)2(µ-L)] [where
M = Pd() and L = 1–6 or M = Pt() and L = 1, 2, 4, 5 or 7] and
[(PtClMe)2(µ-L)] (where L = 1, 2, 4, 6 or 7) are given in Table 3.
merically pure linear quadridentate NPPN ligands and the
enantiomers of 1, have been prepared via this approach and in
certain cases further reacted with HCl to give the analogous
bis[dichloroplatinum()] complexes. A preliminary study on the
in vitro cytotoxicities of these complexes against the murine
P388 leukaemia tumour cell line has shown that many of the
dinuclear platinum() complexes have comparable activity to
that of cisplatin and clearly indicates that further investigation
of their antiproliferative properties is warranted.
Preliminary biological studies
The in vitro cytotoxicities of the dinuclear complexes [(MCl2)2-
(µ-L)] [where M = Pd() and L = 1 or 5 or M = Pt() and L = 1,
2, 4, 5 or 6] and [(PtClMe)2(µ-L)] (where L = 1, 2, 4, 6 or 7) have
been assessed by measuring the effect on proliferation of the
murine P388 leukaemia tumour cell line. The IC50 values (con-
centrations resulting in 50% inhibition of labeled thymidine)
for these complexes and the reference compound cisplatin are
summarised in Table 4. Several of the dinuclear platinum()
complexes had activities comparable to that of cisplatin. All of
the bis[dichloropalladium()] complexes and the two dinuclear
platinum() complexes containing 5 that were tested, however,
had significantly lower activities than cisplatin. In addition, a
small but significant difference in activity was observed between
the two enantiomeric complexes [(PtClMe)2{µ-(RP,RP)-1}]
and [(PtClMe)2{µ-(SP,SP)-1}] in keeping with that previously
observed for a range of mononuclear platinum() complexes
containing optically active diamines.24 The data also suggest
a similar level of antiproliferative activity for dinuclear
platinum() complexes containing linear quadridentate PNNP
rather than NPPN ligands.
Experimental
Procedures and materials
Reactions involving air-sensitive reagents were performed
under argon using Schlenk techniques. Solvents were dried and
purified by distillation under argon. NMR spectra were
recorded on a Varian Gemini II spectrometer operating at
300 MHz (1H) or 121 MHz (31P-{1H}). Chemical shifts are
reported as δ values relative to SiMe4 (1H) or 85% H3PO4
(31P-{1H}). Optical rotations were measured with an Optical
Activity AA-10 or a Perkin-Elmer Model 241 polarimeter on
the specified solutions in 1 dm cells at 20 ЊC. Elemental analyses
were performed by staff within the Research School of
Chemistry.
The compounds ( )-(2-aminophenyl)phenylphosphine,11
(RP*,RP*)- and (RP*,SP*)-1,3-bis[(2-aminoethyl)phenylphos-
phino]propane, (RP*,RP*)- and (RP*,SP*)-5,1 di-µ-chloro-bis[2-
(dimethylaminomethyl)phenyl-C1,N]dipalladium(), 8,12 1,3-
bis[(2-diphenylphosphinophenyl)amino]propane, 6,5 [SP-4-2]-
chloro(cycloocta-1,5-diene)methylplatinum(),16 1,2-bis[(2-di-
phenylphosphinophenyl)amino]ethane, 7,7 and di-µ-chloro-
bis{(S)-2-[1-(dimethylamino)ethyl]phenyl-C1,N}dipalladium-
(), (S)-9,15 were prepared by literature procedures.
Conclusion
A general method has been devised for the separation of the
racemic and meso diastereomers of linear quadridentate NPPN
ligands via fractional crystallisation of a pair of dinuclear
palladium() complexes containing the respective ligand and
orthometallated N,N-dimethylbenzylamine. The diastereo-
merically pure complexes were readily converted to the
analogous bis[dichloropalladium()] compounds by reaction
with HCl and the ligand diastereomers themselves obtained
upon further treatment with aqueous KCN. A similar approach
using optically active (S)-dimethyl(1-phenylethyl)amine instead
Preparations
(RP*,RP*)- and (RP*,SP*)-1,3-bis(2-aminophenyl)phenylphos-
phino]propane, (RP*,RP*)- and (RP*,SP*)-1. Sodium foil
(0.788 g, 0.0343 mol) was added to a solution of ( )-(2-
aminophenyl)phenylphosphine (6.90 g, 0.0343 mol) in thf (100
cm3) and the resulting red solution allowed to stir overnight.
The reaction mixture was cooled to Ϫ78 ЊC and a solution of
1,3-dibromopropane (3.46 g, 0.0171 mol) in thf (50 cm3) added
dropwise with stirring. The reaction mixture was allowed to
come to ambient temperature and stirred for a further 48 h. An
aqueous solution of ammonium chloride (20% w/w, 5 cm3) was
of N,N-dimethylbenzylamine has also provided
a viable
method of resolution of the linear quadridentate NPPN ligand
(RP*,RP*)-1,3-bis(2-aminophenyl)phenylphosphino]propane,
(RP*,RP*)-1. A viable synthetic route has also been devised for
the preparation of dinuclear platinum() complexes containing
linear quadridentate P2N2 ligands that involves reaction of
the respective ligand with two equivalents of [PtCl(Me)(cod)].
Several bis[chloro(methyl)platinum()] containing diastereo-
J. Chem. Soc., Dalton Trans., 2002, 234–243
239

View Article Online
Table 3 Selected 1H and 31P-{1H} NMR data for the quadridentate ligands L and the dinuclear complexes [(MCl2)2(µ-L)] [where M = Pd() or Pt()]
and [(PtClMe)2(µ-L)]
31P-{1H}
1H
L
δ(P)
δ(PtMe)
δ(CCH2C)
δ(PCH2)
δ(NCH2)
δ(NH2)
δ(Aromatics)
(a) Ligandsa
(RP*,RP*)-1
(RP,RP)-1
Ϫ34.9s
Ϫ34.9s
Ϫ34.9s
Ϫ35.0s
Ϫ34.0s
Ϫ34.7s
Ϫ33.9s
Ϫ30.8s
Ϫ30.8s
—
—
—
—
—
—
—
—
—
1.67m
1.67m
1.67m
1.70m
1.59m
1.46m
1.42m
1.46m
1.46m
2.21m
2.21m
2.21m
2.22m
2.03m
2.01m
2.00m
1.80m
1.79m
—
—
—
—
—
—
—
2.72m
2.68m
4.11bs
4.11bs
4.11bs
4.12bs
4.12bs
4.38bs
4.10bs
1.46bs
1.46bs
6.62–7.37m
6.62–7.37m
6.62–7.37m
6.60–7.42m
6.63–7.36m
6.63–7.39m
6.63–7.40m
7.11–7.47m
7.25–7.60m
(SP,SP)-1
(RP*,SP*)-1
(RP*,RP*)-2
(RP*,RP*)-3b
(RP*,RP*)-4
(RP*,RP*)-5c
(RP*,SP*)-5c
(b) [(PdCl2)2(µ-L)]d
(RP*,RP*)-1
(RP,RP)-1
e
e
e
e
e
e
e
e
47.9s
47.9s
47.9s
48.5s
51.2s
51.1s
51.2s
51.2s
12.2s, 17.4s
64.7s, 65.3s
9.2s, 18.1s
63.5s, 64.2s
43.4s, 44.4s
—
—
—
—
—
—
—
—
—
1.78m
1.78m
1.78m
1.75m, 2.15m
1.37m, 2.05m
1.48m, 2.02m
1.50m, 1.85m
1.41m, 1.81m
1.85m, 2.27m
2.91m, 3.21m
2.91m, 3.21m
2.91m, 3.21m
2.70m, 2.91m
2.66m
2.65m
2.75m
—
—
—
—
—
—
—
—
7.29–7.91m
7.29–7.91m
7.29–7.91m
7.41–7.97m
7.42–7.82m
7.39–7.84m
7.67–8.05m
7.41–7.81m
7.56–8.17m
(SP,SP)-1
(RP*,SP*)-1
(RP*,RP*)-2
(RP*,SP*)-2
(RP*,RP*)-3
(RP*,RP*)-4
(RP*,RP*)-5
2.58m
2.70m, 2.82m
3.17m
5.45bs
(RP*,SP*)-5
—
—
1.90m, 2.28m
1.55m
2.70m, 2.80m
3.18m
5.32bs
7.40–8.25m
6.99–8.90m
e
6
—
3.03m, 3.90m
(c) [(PtCl2)2(µ-L)]d, f
(RP*,RP*)-1
e
e
e
e
19.2s(3770)
19.7s(3888)
22.0s(3844)
21.8s(3850)
32.2bs(3680)
Ϫ6.4bs(3402)
31.2bs(3860)
Ϫ8.8bs(3360)
16.2s(3917)
16.7s(3912)
—
—
—
—
—
1.77m
1.09m
1.35m, 2.00m
1.24m, 1.38m
2.05m, 2.32m
2.50m
2.75m
2.55m, 2.71m
2.59m
2.70m
—
—
—
—
7.20–8.45m
7.20–8.40m
7.35–8.25m
7.35–8.25m
7.53–8.20m
(RP*,SP*)-1
(RP*,RP*)-2
(RP*,RP*)-4
(RP*,RP*)-5
3.50m
5.80bs
(RP*,SP*)-5
—
—
2.05m, 2.28m
1.44m
2.65m, 2.84m
3.35m
3.64m
5.85bs
7.48–8.33m
7.24–9.35m
e
6
—
(d) [(PtClMe)2(µ-L)]b, f
(RP*,RP*)-1
(RP,RP)-1
e
e
e
e
19.2s(4618)
19.2s(4618)
19.2s(4618)
18.6s(4554)
19.6s(4631)
20.9s(4560)
19.4s(4670)
20.0s(4696)
19.3s(4769)
Ϫ0.08s
Ϫ0.08s
Ϫ0.08s
0.30s
0.54s
0.37s
0.59d
0.64d
0.68s
1.84m
1.84m
1.84m
2.09m
1.49m, 1.73m
1.15m, 1.38m
1.76m
2.57m, 3.39m
2.57m, 3.39m
2.57m, 3.39m
2.70m
2.38m
2.34m, 2.63m
—
—
—
—
—
—
—
3.17m
3.83m
6.55–7.83m
6.55–7.83m
6.55–7.83m
6.50–8.50m
7.09–7.21m
7.29–7.92m
7.01–7.89m
(SP,SP)-1
(RP*,SP*)-1d
(RP*,RP*)-2
(RP*,RP*)-4d
6
5.72bs
6.76bs
e
e
7
—
—
2.04m, 4.60m
7.26–8.17m
1
a In CDCl3. b In (CD3)2CO. c In CD2Cl2. d In (CD3)2SO. e Obscured by the manifold of aromatic resonances. f Values of JPtP are given in Hz in
parentheses.
added and the solvent removed under reduced pressure. Water
(75 cm3) was added to the residue and the solution extracted
with dichloromethane (3 × 40 cm3). The combined organic
extracts were dried (MgSO4), filtered and the solvent removed
under reduced pressure. The solid residue was recrystallised
from hot methanol (100 cm3) to give a white crystalline mass of
(RP*,RP*)- and (RP*,SP*)-1. The product was collected, washed
with cold methanol and dried in vacuo (3.70 g, 49%). [Batch A]
(Found: C, 73.1; H, 6.5; N, 6.0. Calc. for C27H28N2P2: C, 73.3;
phino]butane, (RP*,RP*)- and (RP*,SP*)-2; (RP*,RP*)- and
(RP*,SP*)-1,5-bis[(2-aminophenyl)phenylphosphino]pentane,
(RP*,RP*)- and (RP*,SP*)-3; and (RP*,RP*)- and (RP*,SP*)-1,6-
bis[(2-aminophenyl)phenylphosphino]hexane, (RP*,RP*)- and
(RP*,SP*)-4.
Separation of (RP*,RP*)- and (RP*,SP*)-L. Formation and
separation of the internally diastereomeric complexes [SP-4-2-
(RP*,RP*)]- and [SP-4-2-(RP*,SP*)]-{ꢀ-1,3-bis[(2-aminophenyl)-
phenylphosphino]propane}{bis[2-(dimethylaminomethyl)phenyl-
C1,N]}dipalladium(II) hexafluorophosphate-hydrate (1/2), [{Pd-
(2-C6H4CH2NMe2)}2{ꢀ-(RP*,RP*)-1}](PF6)2 and [{Pd(2-C6H4-
CH2NMe2)}2{ꢀ-(RP*,SP*)-1}](PF6)2. The chloro-bridged dimer
di-µ-chloro-bis[2-(dimethylaminomethyl)phenyl-C1,N]dipal-
ladium(), 8 (4.60 g, 8.33 mmol) and batch A of the linear
quadridentate P2N2 ligand (RP*,RP*)- and (RP*,SP*)-1 (3.69 g,
8.33 mmol) were suspended in methanol (100 cm3) and the
mixture stirred until dissolution was complete. The yellow
1
H, 6.4, N, 6.3%). H NMR (CDCl3): δ 1.67 (m, 2 H, CCH2C),
2.21 (m, 4 H, PCH2), 4.11 (bs, 4 H, NH2), 6.62–7.36 (m, 18 H,
aromatics). 31P-{1H} NMR (CDCl3): δ Ϫ34.9 (s, 2 P), Ϫ35.0 (s,
2 P). m/z: 442, (Mϩ); 365, (M Ϫ C6H5)ϩ; 350, (M Ϫ C6H5NH2)ϩ;
242, (M Ϫ C6H5PC6H4NH2)ϩ. A second crop of crystals was
obtained on reducing the volume of the filtrate by ca. 50%
(2.03 g, 27%). [Batch B]
The following compounds were prepared in a similar manner:
(RP*,RP*)- and (RP*,SP*)-1,4-bis[(2-aminophenyl)phenylphos-
240
J. Chem. Soc., Dalton Trans., 2002, 234–243

View Article Online
methylaminomethyl)phenyl-C1,N]}dipalladium()
hexa-
Table 4 IC50 values for selected dinuclear complexes of the type
[(MCl2)2(µ-L)] [where M = Pd() or Pt()] and [(PtClMe)2(µ-L)] against
the murine P388 leukaemia tumour cell line
fluorophosphate-hydrate (1/1), [{Pd(2-C6H4CH2NMe2)}2{µ-
(RP*,RP*)-2}](PF6)2 and [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,
SP*)-2}](PF6)2; [SP-4-2-(RP*,RP*)]- and [SP-4-2-(RP*,SP*)]-
{µ-1,5-bis[(2-aminophenyl)phenylphosphino]pentane}{bis[2-
IC50/µmol dmϪ3 a
(dimethylaminomethyl)phenyl-C1,N]}dipalladium()
hexa-
L
[(PtClMe)2(µ-L)]
[(PtCl2)2(µ-L)]
[(PdCl2)2(µ-L)]
fluorophosphate, [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,RP*)-3}]-
(PF6)2 and [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,SP*)-3}](PF6)2;
(RP*,RP*)-1
(RP*,SP*)-1
(RP,RP)-1
(SP,SP)-1
(RP*,RP*)-2
(RP*,RP*)-4
(RP*,RP*)-5
(RP*,SP*)-5
6
0.9
30
5.6
1.5
1.0
3.4
—
—
0.44
1.9
65
90
—
—
0.1
0.14
65
70
—
—
—
[SP-4-2-(RP*,RP*)]-
aminophenyl)phenylphosphino]hexane}{bis[2-(dimethylamino-
methyl)phenyl-C1,N]}-dipalladium()
hexafluorophosphate,
and
[SP-4-2-(RP*,SP*)]-{µ-1,6-bis[(2-
[{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,RP*)-4}](PF6)2 and [{Pd(2-
C6H4CH2NMe2)}2{µ-(RP*,SP*)-4}](PF6)2; [SP-4-2-(RP*,RP*)]-
and [SP-4-2-(RP*,SP*)]-{µ-1,3-bis[(2-aminoethyl)phenylphos-
phino]propane}{bis[2-(dimethylaminomethyl)phenyl-C1,N]}di-
palladium() hexafluorophosphate-hydrate (1/1), [{Pd(2-C6H4-
CH2NMe2)}2{µ-(RP*,RP*)-5}](PF6)2 and [{Pd(2-C6H4CH2-
NMe2)}2{µ-(RP*,SP*)-5}](PF6)2; and [SP-4-2]-{µ-1,3-bis[(2-di-
phenylphosphinophenyl)amino]propane}{bis[2-(dimethyl-
aminomethyl)phenyl-C1,N]}dipalladium() hexafluorophos-
phate, [{Pd(2-C6H4CH2NMe2)}2(µ-6)](PF6)2.
—
b
65
b
b
0.12
—
—
—
7
a An IC50 value of 1.1 µmol dmϪ3 was obtained for the reference com-
pound cis-[PtCl2(NH3)2]. b The IC50 value is >100 µmol dmϪ3 and hence
could not be determined from the concentration range used in the assay.
solution was filtered, a solution of ammonium hexafluoro-
phosphate (1.36 g, 8.33 mmol) in water (5 cm3) was added
dropwise and the mixture stirred for 2 h. The resulting white
precipitate of diastereomerically pure [{Pd(2-C6H4CH2-
NMe2)}2{µ-(RP*,RP*)-1}](PF6)2 was collected, washed with
methanol (2 × 5 cm3) and dried in vacuo (6.14 g, 61%). Com-
plete removal of chloride ion from the sample was achieved by
dissolving the complex (0.50 g, 0.412 mmol) in acetone (50 cm3)
followed by the addition of a solution of ammonium hexa-
fluorophosphate to give [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,
RP*)-1}](PF6)2 (0.45 g, 90%), mp 226–227 ЊC. (Found: C, 42.9;
H, 4.5; N, 4.5. Calc. for C45H52F12N4P4Pd2ؒ2H2O: C, 43.2; H,
[SP-4-2-(RP*,RP*)]-{ꢀ-1,3-Bis[(2-aminophenyl)phenylphos-
phino]propane}bis[dichloropalladium(II)]hydrochloride
(2/1),
[(PdCl2)2{ꢀ-(RP*,RP*)-1}]. The complex [{Pd(2-C6H4CH2-
NMe2)}2{µ-(RP*,RP*)-1}](PF6)2 (3.12 g, 2.57 mmol) was sus-
pended in methanol (100 cm3), hydrochloric acid (10 M, 10 cm3)
was added and the solution refluxed overnight. The yellow
crystals of [(PdCl2)2{µ-(RP*,RP*)-1}] that formed were col-
lected, washed with diethyl ether–methanol (9 : 1, 10 cm3) and
dried in vacuo (2.02 g, 99%), mp 248 ЊC (decomp.). (Found:
C, 39.9; H, 3.8; N, 3.4. Calc. for C27H28Cl4N2P2Pd2ؒ0.5HCl:
1
C, 39.8; H, 3.5, N, 3.4%). H NMR [(CD3)2SO]: δ 1.78 (m,
1
2 H, CCH2C), 2.91 (m, 2 H, PCHH), 3.21 (m, 2 H, PCHH),
7.29–7.91 (m, 22 H, aromatics and NH2). 31P-{1H} NMR
[(CD3)2SO]: δ 47.9 (s, 2 P).
The following compounds were prepared in a similar manner:
[SP-4-2-(RP*,SP*)]-{µ-1,3-bis[(2-aminophenyl)phenylphos-
phino]propane}bis[dichloropalladium()]hydrochloride (1/1),
4.5; N, 4.5%). H NMR [(CD3)2CO]: δ 1.93 (m, 2 H, CCH2C),
3
2.77 (m, 4 H, PCH2), 2.77 (bs, 6 H, NMe), 2.93 (d, 6 H, JPH
2
9 Hz, NMe), 3.60, 4.15 (bAB q, 4 H, JAB 14 Hz, CH2NMe2),
6.68 (bs, 4 H, NH2), 6.93–8.01 (m, 26 H, aromatics). 31P-{1H}
NMR [(CD3)2CO]: δ 39.8 (s, 2 P).
Excess ammonium hexafluorophosphate (2.72 g, 16.7 mmol)
in water (15 cm3) was added dropwise to the filtrate from
the isolation of [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,RP*)-1}]X2.
Water (50 cm3) was added and the resulting white precipitate
enriched in [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,SP*)-1}](PF6)2
was collected, washed with water (5 cm3), methanol–diethyl
ether (1 : 9, 5 cm3) and finally diethyl ether (5 cm3) and dried in
vacuo (3.02 g, 30%). 31P-{1H} NMR [(CD3)2CO]: δ 37.1 (s, 2 P),
39.8 (s, 2 P).
[(PdCl2)2{µ-(RP*,SP*)-1}];
[SP-4-2-(RP*,RP*)]-{µ-1,4-bis[(2-
aminophenyl)phenylphosphino]butane}bis[dichloropalladium-
()]hydrochloride (1/1), [(PdCl2)2{µ-(RP*,RP*)-2}]; [SP-4-2-
(RP*,SP*)]-{µ-1,4-bis[(2-aminophenyl)phenylphosphino]-
butane}bis[dichloropalladium()]hydrochloride (1/1), [(Pd-
Cl2)2{µ-(RP*,SP*)-2}]; [SP-4-2-(RP*,RP*)]-{µ-1,5-bis[(2-amino-
phenyl)phenylphosphino]pentane}bis[dichloropalladium()],
[(PdCl2)2{µ-(RP*,RP*)-3}];
[SP-4-2-(RP*,RP*)]-{µ-1,6-bis[(2-
aminophenyl)phenylphosphino]hexane}bis[dichloropalladium-
()], [(PdCl2)2{µ-(RP*,RP*)-4}]; [SP-4-2-(RP*,RP*)]-{µ-1,3-bis-
[(2-aminoethyl)phenylphosphino]propane}bis[dichloropalla-
dium()]hydrochloride (1/3), [(PdCl2)2{µ-(RP*,RP*)-5}]; [SP-4-
2-(RP*,SP*)]-{µ-1,3-bis[(2-aminoethyl)phenylphosphino]pro-
pane}bis[dichloropalladium()]hydrochloride (2/5), [(PdCl2)2-
{µ-(RP*,SP*)-5}]; and [SP-4-2]-{µ-1,3-bis[(2-diphenylphos-
phinophenyl)amino]propane}bis[dichloropalladium()]-
hydrate (1 : 2), [(PdCl2)2(µ-6)].
The above procedure was repeated using batch B of
(RP*,RP*)- and (RP*,SP*)-1 (2.00 g, 4.51 mmol) and 6 (2.49 g,
4.51 mmol) to give pure [{Pd(2-C6H4CH2NMe2)}2{µ-
(RP*,RP*)-1}](PF6)2 (0.665 g, 15%) and a hexafluorophosphate
salt enriched in [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,SP*)-1}]-
(PF6)2 (2.41 g, 58%).
The meso-enriched hexafluorophosphate salt (5.43 g, 4.5
mmol) was dissolved in hot methanol (200 cm3), the solution
filtered and the volume of filtrate reduced by ca. 50% to give
diastereomerically pure [{Pd(2-C6H4CH2NMe2)}2{µ-(RP*,SP*)-
1}](PF6)2 as fine white needles. The complex was collected,
washed with methanol–diethyl ether (1 : 9, 5 cm3) followed by
diethyl ether (5 cm3) and dried in vacuo (3.98 g, 73%), mp 250–
252 ЊC. (Found: C, 42.7; H, 4.5; N, 4.4. Calc. for C45H52F12-
(RP*,RP*)-1,3-Bis[(2-aminophenyl)phenylphosphino]propane-
hydrate (2/1), (RP*,RP*)-1. To a suspension of [(PdCl2)2{µ-
(RP*,RP*)-1}] (4.28 g, 5.37 mmol) in methanol (150 cm3) was
added petroleum spirit (bp 40–60 ЊC) (75 cm3) and potassium
cyanide (3.36 g, 0.0500 mol) and the mixture shaken thoroughly
until there was no further change in the colour of the solution.
Dichloromethane (100 cm3) and water (70 cm3) were added, the
mixture shaken and the layers separated. The aqueous layer was
extracted with dichloromethane (1 × 50 cm3). The combined
organic extracts were washed with water (1 × 50 cm3) and the
aqueous extract washed with dichloromethane (1 × 30 cm3).
The combined organic extracts were dried (MgSO4), filtered
and the solvent removed under reduced pressure. The residue
1
N4P4Pd2ؒ2H2O: C, 43.2; H, 4.5; N, 4.5%). H NMR [(CD3)2-
CO]: δ 1.75 (m, 1 H, CCHHC), 2.22 (m, 1 H, CCHHC), 2.88
3
(m, 4 H, PCH2), 2.93 (d, 6 H, JPH 9 Hz, NMe), 3.00 (bs, 6 H,
2
4
NMe), 3.78, 4.31 (AB part of ABX m, 4 H, JAB 14 Hz, JAX
4
3 Hz, JBX ≈ 0 Hz, CH2NMe2), 6.62–7.86 (m, 30 H, aromatics
and NH2). 31P-{1H} NMR [(CD3)2CO]: δ 37.1 (s, 2 P).
The following compounds were prepared and separated in a
similar manner: [SP-4-2-(RP*,RP*)]- and [SP-4-2-(RP*,SP*)]-
{µ-1,4-bis[(2-aminophenyl)phenylphosphino]butane}{bis[2-(di-
J. Chem. Soc., Dalton Trans., 2002, 234–243
241

View Article Online
was recrystallised from hot methanol (100 cm3) to give
(RP*,RP*)-1 as fine white needles. A further crop of (RP*,RP*)-1
was obtained upon reduction of the volume of the mother
liquor by ca. 70%. The combined product was washed with cold
methanol (2 × 5 cm3) and dried in vacuo (1.97 g, 83%), mp 148–
150 ЊC. (Found: C, 72.3; H, 6.2; N, 6.2. Calc. for C27H28N2P2ؒ
0.5H2O: C, 71.8; H, 6.5, N, 6.2%). 1H NMR (CDCl3): δ 1.67 (m,
2 H, CCH2C), 2.21 (m, 4 H, PCH2), 4.11 (bs, 4 H, NH2), 6.62–
7.37 (m, 18 H, aromatics). 31P-{1H} NMR (CDCl3): δ Ϫ34.9 (s,
2 P).
The following compounds were prepared in a similar manner:
(RP*,SP*)-1,3-bis[(2-aminophenyl)phenylphosphino]propane-
hydrate (2/1), (RP*,SP*)-1; (RP*,RP*)-1,4-bis[(2-aminophenyl)-
phenylphosphino]butane, (RP*,RP*)-2; (RP*,RP*)-1,5-bis[(2-
aminophenyl)phenylphosphino]pentane, (RP*,RP*)-3; (RP*,
RP*)-1,6-bis[(2-aminophenyl)phenylphosphino]hexane, (RP*,
RP*)-4; (RP*,RP*)-1,3-bis[(2-aminoethyl)phenylphosphino]pro-
pane, (RP*,RP*)-5; and (RP*,SP*)-1,3-bis[(2-aminoethyl)phenyl-
phosphino]propane, (RP*,SP*)-5.
mp 248 ЊC (decomp.), α Ϫ72Њ (589 nm, c 0.306 g per 100 cm3,
CH2Cl2). (Found: C, 39.5; H, 3.7; N, 3.5. Calc. for C27H28-
1
Cl4N2P2Pd2ؒH2O: C, 39.8; H, 3.7; N, 3.4%). H and 31P-{1H}-
NMR: identical to that of [(PdCl2)2{µ-(RP*,RP*)-1}].
[SP-4-2-(SP,SP)]-{ꢀ-1,3-Bis[(2-aminophenyl)phenylphosphino]-
propane}bis[dichloropalladium(II)]hydrochloride (1/1), [(PdCl2)2-
{ꢀ-(SP,SP)-1}]. Prepared in a similar manner to [(PdCl2)2{µ-
(RP*,RP*)-1}] except using (SP,SP,S,S)-10 (1.24 g, 1.0 mmol) to
give yellow crystals of [(PdCl2)2{µ-(SP,SP)-1}] (0.65 g, 82%), mp
248 ЊC (decomp.), α ϩ72Њ (589 nm, c 0.123 g per 100 cm3,
CH2Cl2). (Found C, 38.6; H, 3.5; N, 3.1. Calc. for C27H28-
1
Cl4N2P2Pd2ؒHCl: C, 38.9; H, 3.5; N, 3.4%). H and 31P-{1H}-
NMR: identical to that of [(PdCl2)2{µ-(RP*,RP*)-1}].
(RP,RP)-1,3-Bis(2-aminophenyl)phenylphosphino]propane,
(RP,RP)-1. Prepared in a similar manner to (RP*,RP*)-1 except
using [(PdCl2)2{µ-(SP,SP)-1}] (0.40 g, 0.50 mmol) to give white
crystals of (RP,RP)-1 (0.22 g, 97%), mp 149–150 ЊC, α ϩ65Њ (589
1
nm, c 0.305 g per 100 cm3, CH2Cl2). H and 31P-{1H}NMR:
identical to that of (RP*,RP*)-1.
Resolution of (RP*,RP*)-1. Formation and separation of the
internally diastereomeric complexes [SP-4-2-(RP,RP,S,S)]- and
[SP-4-2-(SP,SP,S,S)]-{ꢀ-1,3-bis[(2-aminophenyl)phenylphos-
phino]propane}{bis[2-(1-dimethylaminoethyl)phenyl-C1,N]}dipal-
ladium(II) hexafluorophosphate, (RP,RP,S,S)- and (SP,SP,S,S)-
10. The optically active, chloro-bridged dimer di-µ-chloro-bis-
{(S)-2-[1-(dimethylamino)ethyl]phenyl-C1,N}dipalladium(),
(S)-9 (2.49 g, 4.29 mmol) and (RP*,RP*)-1 (1.90 g, 4.29 mmol)
were suspended in methanol (100 cm3) and the mixture
stirred until dissolution was complete. The yellow solution was
filtered and excess ammonium hexafluorophosphate (2.18 g,
13.4 mmol) in water (20 cm3) was added dropwise followed by
the dropwise addition of water (40 cm3). The resulting white
precipitate was isolated by filtration, washed with cold metha-
nol (5 cm3) and dried in vacuo (4.67 g, 87%). 31P-{1H} NMR
[(CD3)2CO]: δ 36.8 (s, 1 P), 37.5 (s, 2 P). The diastereomeric
mixture of hexafluorophosphate salts (4.54 g, 3.66 mmol) was
dissolved in the minimum volume of acetone (120 cm3) and
diethyl ether (25 cm3) was added dropwise to give white prisms
of (SP,SP,S,S)-10. The complex was collected, washed with
diethyl ether (2 × 2 cm3) and dried in vacuo (1.34 g, 59%), mp
203 ЊC (decomp.), α ϩ128Њ (589 nm, c 0.307 g per 100 cm3,
acetone). (Found: C, 45.1; H, 4.9; N, 4.3. Calc. for C47H56F12-
N4P4Pd2: C, 45.5; H, 4.5, N, 4.5%). 1H NMR [(CD3)2CO]: δ 1.60
(SP,SP)-1,3-Bis(2-aminophenyl)phenylphosphino]propane,
(SP,SP)-1. Prepared in a similar manner to (RP*,RP*)-1 except
using [(PdCl2)2{µ-(RP,RP)-1}] (0.31 g, 0.39 mmol) to give white
crystals of (SP,SP)-1 (0.15 g, 85%), mp 149–150 ЊC, α Ϫ65Њ (589
nm, c 0.306 g per 100 cm3, CH2Cl2). H and 31P-{1H}NMR:
1
identical to that of (RP*,RP*)-1.
[SP-4-2-(RP*,RP*)]-{ꢀ-1,3-Bis[(2-aminophenyl)phenylphos-
phino]propane}bis[chloromethylplatinum(II)],
[(PtClMe)2{ꢀ-
(RP*,RP*)-1}]. To a solution of (RP*,RP*)-1 (0.08 g, 0.181
mmol) in thf (5 cm3) was added a solution of [PtClMe(cod)]
(0.13 g, 0.362 mmol). Petroleum spirit (bp 40–60 ЊC) (20 cm3)
was added and the resulting white precipitate of [(PtClMe)2{µ-
(RP*,RP*)-1}] was collected, washed with petroleum spirit
(5 cm3) and diethyl ether (5 cm3) and dried in vacuo (0.13 g,
1
77%), mp 244 ЊC (decomp.). H NMR (CD2Cl2): δ Ϫ0.08 (s,
6 H, 2JPtH 78 Hz, PtMe), 1.84 (m, 2 H, CCH2C), 2.57 (m, 2 H,
PCHH), 3.39 (m, 2 H, PCHH), 6.55–7.83 (m, 22 H, aromatics
and NH2). 31P-{1H} NMR (CD2Cl2): δ 19.2 (s, 2 P, JPtP 4618
1
Hz).
The following compounds were prepared in a similar manner:
[SP-4-2-(RP*,SP*)]-{µ-1,3-bis[(2-aminophenyl)phenylphos-
phino]propane}bis[chloromethylplatinum()], [(PtClMe)2{µ-
3
(d, 6 H, JHH 6.5 Hz, CMe), 1.93 (m, 2 H, CCH2C), 2.72 (bs,
6 H, NMe), 2.81 (m, 2 H, PCHH), 2.90 (bs, 6 H, NMe), 3.19 (m,
2 H, PCHH), 3.82 (dq, 2 H, 3JHH 6.5 Hz, 4JPH 6.5 Hz, CHMe),
6.71–7.96 (m, 30 H, aromatics and NH2). 31P-{1H} NMR
[(CD3)2CO]: δ 37.5 (s, 2 P).
(RP*,SP*)-1}];
[SP-4-2-(RP,RP)]-{µ-1,3-bis[(2-aminophenyl)-
phenylphosphino]propane}bis[chloromethylplatinum()]hy-
drate (1/1), [(PtClMe)2{µ-(RP,RP)-1}]; [SP-4-2-(SP,SP)]-{µ-1,3-
bis[(2-aminophenyl)phenylphosphino]propane}-bis[chloro-
The filtrate from the isolation of (SP,SP,S,S)-10 was evapor-
ated to dryness and re-dissolved in acetone (16 cm3). Diethyl
ether (30 cm3) was added dropwise to give a product enriched
in (RP,RP,S,S)-10 (1.23 g). The isolated complex was again dis-
solved in acetone (12 cm3) and diethyl ether (15 cm3) added
dropwise to give white needles of pure (RP,RP,S,S)-10 (1.03 g,
45%), mp 212 ЊC (decomp.), α Ϫ19Њ (589 nm, c 0.310 g per
100 cm3, acetone). (Found C, 45.6; H, 4.4; N, 4.2. Calc. for
C47H56F12N4P4Pd2: C, 45.5; H, 4.5, N, 4.5%). 1H NMR
methylplatinum()]tetrahydrofuran
(SP,SP)-1}]; [SP-4-2-(RP*,RP*)]-{µ-1,4-bis[(2-aminophenyl)-
(2/1),
[(PtClMe)2{µ-
phenylphosphino]butane}bis[chloromethylplatinum()]hydrate
(1/2), [(PtClMe)2{µ-(RP*,RP*)-2}]; [SP-4-2-(RP*,RP*)]-{µ-1,6-
bis[(2-aminophenyl)phenylphosphino]hexane}bis[chloro-
methylplatinum()]hydrate (1/1), [(PtClMe)2{µ-(RP*,RP*)-4}];
[SP-4-2]-{µ-1,3-bis[(2-diphenylphosphinophenyl)amino]pro-
pane}bis[chloromethylplatinum()]hydrate (1/3), [(PtClMe)2(µ-
6)]; and [SP-4-2]-{µ-1,2-bis[(2-diphenylphosphinophenyl)-
amino]ethane}bis[chloromethylplatinum()]hydrate (1 : 2), [(Pt-
ClMe)2(µ-7)].
3
[(CD3)2CO]: δ 1.46 (d, 6 H, JHH 6.5 Hz, CMe), 1.83 (m, 2 H,
CCH2C), 2.73 (m, 2 H, PCHH), 2.88 (d, 6 H, 4JPH 6 Hz, NMe),
2.90 (bs, 6 H, NMe), 3.12 (m, 2 H, PCHH), 3.82 (dq, 2 H, 3JHH
6.5 Hz, 4JPH 6 Hz, CHMe), 6.59–7.98 (m, 30 H, aromatics and
NH2). 31P-{1H} NMR [(CD3)2CO]: δ 36.8 (s, 2 P).
[SP-4-2-(RP*,RP*)]-{ꢀ-1,3-Bis[(2-aminophenyl)phenylphos-
phino]propane}bis[dichloroplatinum(II)]tetrahydrofuran
(2/1),
[(PtCl2)2{ꢀ-(RP*,RP*)-1}]. An excess of hydrochloric acid (10
M, 5 cm3) was added to a suspension of [(PtClMe)2{µ-
(RP*,RP*)-1}] (0.08 g, 0.0857 mmol) in thf (10 cm3) and the
mixture stirred overnight. Water (10 cm3) was added and the
solution stirred for 30 min. The resulting white precipitate of
[(PtCl2)2{µ-(RP*,RP*)-1}] was collected, washed with diethyl
[SP-4-2-(RP,RP)]-{ꢀ-1,3-Bis[(2-aminophenyl)phenylphos-
phino]propane}bis[dichloropalladium(II)]hydrate (1/1), [(PdCl2)2-
{ꢀ-(RP,RP)-1}]. Prepared in a similar manner to [(PdCl2)2{µ-
(RP*,RP*)-1}] except using (RP,RP,S,S)-10 (0.90 g, 0.72 mmol)
to give yellow crystals of [(PdCl2)2{µ-(RP,RP)-1}] (0.50 g, 87%),
242
J. Chem. Soc., Dalton Trans., 2002, 234–243

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ether (5 cm3) and dried in vacuo (0.06 g, 75%), mp 263 ЊC
(decomp.). (Found: C, 34.4; H, 3.3; N, 3.0. Calc. for C27H28-
Cl4N2P2Pt2ؒ0.5C4H8O: C, 34.5; H, 3.2; N, 2.8%). 1H NMR
[(CD3)2SO]: δ 1.77 (m, 4 H, CCH2C and thf ), 2.50 (m, 4 H,
PCH2), 3.60 (m, 2 H, thf ), 7.20–8.45 (m, 22 H, aromatics and
NH2). 31P-{1H} NMR [(CD3)2SO]: δ 19.2 (s, 2 P, 1JPtP 3770 Hz).
The following compounds were prepared in a similar manner:
[SP-4-2-(RP*,SP*)]-{µ-1,3-bis[(2-aminophenyl)phenylphos-
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X-Ray crystallography
Crystal data for complex (SP,SP,S,S)-10. C51.5H65Cl0.5F9N4-
O1.5P3.5Pd2, M = 1274.07, orthorhombic, a = 17.622(4), b =
21.207(3), c = 16.001(3) Å, U = 5980(3) Å3, T = 193 K, space
group P21212 (no. 18), Z = 4, µ(Cu-Kα) = 65.1 cmϪ1, 9587 reflec-
tions measured, 8883 unique (Rint = 0.066) which were used in
all calculations. The final R and RЈ values on 7442 reflections
with I > 3σ(I ) being 0.060 and 0.112 for constrained refinement
using 260 variables.
The data were collected using a Rigaku AFC6R diffracto-
meter at Ϫ80 ЊC. The starting structure was determined by
direct methods.25 The structure exhibits pseudo symmetry and
is a displacive modulation of a I222 parent structure. There
Ϫ
is also disorder of the PF6 anions and one acetone molecule.
Calculations were performed using the TEXSAN and
RAELS96 crystallographic software packages.26,27 Details of
the disorder, pseudo symmetry and refinement are given in the
CIF.
CCDC reference number 169728.
See http://www.rsc.org/suppdata/dt/b1/b106861j/ for crystal-
lographic data in CIF or other electronic format.
Biological procedures and materials
P388 leukaemia cells were cultured in Dulbecco’s Modified
Eagle Medium H16 with 10% horse serum (herein EC10). All
cells were cultured and incubated in a Froma Scientific Infrared
CO2 incubator at 37 ЊC in 5% CO2. Cell suspensions were
centrifuged using a Jouan centrifuge model CR 4 22. Linbro 96
round bottom cell tissue culture plates were used for the
thymidine incorporation assay. Cells were harvested using a
Pharmacia Version 1.02 Micro Cell Harvester and incorporated
thymidine was counted using a Pharmacia 1205 Betaplate
liquid scintillation counter. Thymidine incorporation assays
were performed following a literature procedure,28 the com-
pounds tested being dissolved in dimethylsulfoxide (0.2 cm3)
to give a concentration of 0.02 mol dmϪ3 and then diluted to
2 × 10Ϫ5 mol dmϪ3 using EC10.
25 SIR 92, A. Altomare, M. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori and M. Camalli, J. Appl. Crystallogr., 1994,
27, 435.
26 TEXSAN, Crystal Structure Analysis Software, Version 1.8,
Molecular Structure Corporation, Houston, TX, 1997.
27 RAELS96: A. D. Rae, A Comprehensive Constrained Least-Square
Refinement Program, The Australian National University, Canberra,
Australia, 1996.
28 L. Hudson and F. C. Hay, Practical Immunology, 3rd edn., Blackwell
Scientific Publications, London, 1989, p. 430.
J. Chem. Soc., Dalton Trans., 2002, 234–243
243