SCHOOL OF ADVANCED STUDIES
Doctorate course in
Chemical Sciences
PhD thesis
New scorpionate ligands
and relative metal complexes with
biomimetic and cytotoxic activity
Cycle XIX
Scientific-Sector CHIM/03
PhD candidate
Dr. Simone Alidori
Tutor
Prof. Carlo Santini
2003/04 – 2005/06
1
INDEX
Chapter 1
Introduction ______________________________________________________________________________________ 5
1. Polypyrazolylborate and Scorpionate Ligands ________________________________________________________ 5
1.1.
Abbreviation System _____________________________________________________________________ 7
1.2.
Preparation of poly(pyrazolyl)borates _______________________________________________________ 8
1.3.
Bpx Ligands___________________________________________________________________________ 10
1.3.1. Specific Bpx Ligands ____________________________________________________________________ 12
1.4.
Tpx Ligands ___________________________________________________________________________ 15
1.4.1. Regiochemistry in ligand synthesis _________________________________________________________ 16
1.4.2. Steric effects __________________________________________________________________________ 17
1.4.3. Electronic effects_______________________________________________________________________ 19
1.4.4. Coordination modes ____________________________________________________________________ 20
1.5.
Soft S-donor scorpionates ________________________________________________________________ 23
1.5.1. Hydrobis(mercaptoimidazolyl)borates (Bmx) _________________________________________________ 23
1.5.2. Hydrotris(mercaptoimidazolyl)borates (Bmx) _________________________________________________ 24
1.5.3. Other S3-donor Scorpionates _____________________________________________________________ 26
1.6.
Poly(imidazolyl)borates _________________________________________________________________ 27
1.6.1. Poly-(triazolyl)- (HnB(tz)4-n), –(tetrazolyl)-borates (HnB(tet)4-n) __________________________________ 27
1.6.2. Poly(benzotriazolyl)Borates (HnB(Btz)4-n) ___________________________________________________ 29
1.7.
Poly(pyrazolyl)alkanes __________________________________________________________________ 29
1.7.1. Bis(pyrazolyl)alkanes ___________________________________________________________________ 30
1.7.2. Synthesis of symmetrical bis(pyrazolyl)alkanes _______________________________________________ 32
1.7.3. Tris(pyrazolyl)Alkanes __________________________________________________________________ 35
1.7.4. Synthesis of tris(pyrazolyl)methanes ________________________________________________________ 37
1.8.
Tris(pyrazolyl)MethaneSulfonato __________________________________________________________ 38
2.
Copper and silver derivatives of scorpionates and related ligands ___________________________________ 39
2.1. Copper poly(pyrazol-1-yl)borates _____________________________________________________________ 40
2.1.1. Bis(pyrazol-1-yl)borates (Bpx) derivatives _____________________________________________________ 40
2.1.2. Tris(pyrazol-1-yl)borates (Tpx) derivatives _____________________________________________________ 41
2.1.2. Tetrakis(pyrazol-1-yl)borate (pzoTpx) derivatives ________________________________________________ 42
2.2. Copper poly(triazol-1-yl)borates ______________________________________________________________ 43
2.3. Copper poly(benzotriazol-1)borates ____________________________________________________________ 45
2.4. Copper(I) hydrotris(3-methyl-2-thioxo-1-imidazolyl)borates ________________________________________ 46
2.5. Copper(I) heteroscorpionate derivatives ________________________________________________________ 47
2.6. Copper poly(azol-1-yl)alkanes ________________________________________________________________ 47
2.7. Silver(I) poly(pyrazol-1-yl)borate _____________________________________________________________ 49
2.8. Silver(I) hydrotris(3-methyl-2-thioxo-1-imidazolyl)borates _________________________________________ 53
2.9. Silver(I) poly(imidazolyl)borates ______________________________________________________________ 54
2.10. Silver poly(azolyl)alkanes __________________________________________________________________ 55
Chapter 2
New (diphenylphosphane)benzoic acid copper(I) derivatives of ‘‘scorpionate’’ ligands with superoxide scavenging
activity __________________________________________________________________________________________ 58
1. Experimental section ___________________________________________________________________________ 59
1.1. General procedures _________________________________________________________________________ 59
1.2. Synthesis ________________________________________________________________________________ 60
1.3. {Cu[PPh2(4-C6H4COOH)]2H2B(btz)2} (1) _______________________________________________________ 60
1.4. {Cu[PPh2(2-C6H4COOH)]2H2B(btz)2} (2) _______________________________________________________ 60
1.5. {Cu[PPh2(4-C6H4COOH)]HB(btz)3} (3) ________________________________________________________ 61
1.6. {Cu[PPh2(4-C6H4COOH)]TpMe} (4) ___________________________________________________________ 61
1.7. {Cu[PPh2(4-C6H4COOH)]2pzTp} (5) __________________________________________________________ 62
1.8. {Cu[PPh2(4-C6H4COOH)]2pzTpMe} (6) _________________________________________________________ 62
1.9. {Cu[PPh2(4-C6H4COOH)]2H2B(im)2} (7) _______________________________________________________ 62
2. Results and discussion __________________________________________________________________________ 63
2
Chapter 3
Synthesis, characterization and antioxidant activity of new copper(I) complexes of scorpionate and water soluble
phosphane ligands _________________________________________________________________________________ 70
1. Experimental section ___________________________________________________________________________ 71
1.1. Material and methods _______________________________________________________________________ 71
1.2. Syntheses ________________________________________________________________________________ 71
1.3. {Cu[PPh2(4-C6H4COOH)](Tp4Br)}(1) __________________________________________________________ 72
1.4. {Cu[PPh2(2-C6H4COOH)](Tp4Br)}(2) __________________________________________________________ 72
1.5. {Cu[PPh2(4-C6H4COOH)]2(L2CO2)}(3) ________________________________________________________ 73
1.6. {Cu[TPPTS](Tpms)}(4) _____________________________________________________________________ 73
1.7. Chemiluminescence assay ___________________________________________________________________ 74
1.8. Cell preparation and treatment ________________________________________________________________ 74
1.9. Comet assay ______________________________________________________________________________ 75
1.10. X-ray crystallography ______________________________________________________________________ 75
2. Results and discussion __________________________________________________________________________ 76
2.1. Reaction stoichiometry and spectroscopic data ___________________________________________________ 76
2.2. Structure determination _____________________________________________________________________ 79
2.3. Antioxidant activity ________________________________________________________________________ 82
Chapter 4
A New Ester Substituted Heteroscorpionate Ligand ______________________________________________________ 87
1. Experimental section ___________________________________________________________________________ 88
1.1. General procedures _________________________________________________________________________ 88
1.2. Synthesis of 3-methyl-5-carboxyethylpyrazole ___________________________________________________ 88
1.3. Synthesis of K[BpCOOET,Me] (1) _______________________________________________________________ 89
1.4. Synthesis of Cu(PPh3)(BpCOOET,Me) (2) _______________________________________________________ 89
2. Results and discussion __________________________________________________________________________ 90
Chapter 5
The First Nitro-Substituted Heteroscorpionate Ligand __________________________________________________ 93
1. Experimental _________________________________________________________________________________ 93
1.1. General procedures _________________________________________________________________________ 93
1.2. Synthesis of {Zn[H2B(tzNO2)2]Cl(H2O)2} (2) _____________________________________________________ 94
1.3. Synthesis of {Cd[H2B(tzNO2)2]Cl(H2O)2} (3) _____________________________________________________ 94
2. Results and discussion __________________________________________________________________________ 95
Chapter 6
New Copper(I) phosphane complexes of dihydrobis(3-nitro-1,2,4-triazolyl)borate ligand showing cytotoxic activity ___ 99
1. Materials and methods _________________________________________________________________________ 101
1.1. General procedures ________________________________________________________________________ 101
1.2. Experimental ____________________________________________________________________________ 101
1.3. Synthesis of [H2B (tzNO2)2]Cu[P(m-tolyl)3]2 (1) __________________________________________________ 101
1.4. Synthesis of [H2B (tzNO2)2]Cu[P(p-tolyl)3]2 (2) __________________________________________________ 102
1.5. Synthesis of [H2B(tzNO2)2]Cu[P(C6H5)2(p-C6H4COOH)]2 (3) _______________________________________ 102
1.6. Synthesis of [H2B (tzNO2)2]Cu[P(CH2C6H5)3]2 (4) ________________________________________________ 102
1.7. Synthesis of [H2B (tzNO2)2]Cu[P(p-C6H4F)3]2 (5) _________________________________________________ 102
1.8. Synthesis of [H2B (tzNO2)2]Cu{(C6H5)2PCH2CH2P(C6H5)2} (6) ______________________________________ 103
1.9. Synthesis of [H2B (tzNO2)2]Cu[SeP(C6H5)3] (7) __________________________________________________ 103
1.10. Synthesis of [H2B (tzNO2)2]Cu[P(C6H11)3] (8) __________________________________________________ 103
1.11. Experiments with human cells ______________________________________________________________ 104
1.12. Cell cultures ____________________________________________________________________________ 104
1.13. Cytotoxicity assay _______________________________________________________________________ 104
2. Results and discussion _________________________________________________________________________ 105
2.1. Synthesis and characterization of Cu(I) complexes _______________________________________________ 105
2.2. Cytotoxicity results _______________________________________________________________________ 107
3
Chapter 7
Silver(I)-organophosphane complexes of the dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand __________________ 110
1. Materials and methods _________________________________________________________________________ 110
1.1. General procedures ________________________________________________________________________ 110
2. Experimental section __________________________________________________________________________ 111
2.1. Synthesis _______________________________________________________________________________ 111
2.2. X-ray structure determination for {[H2B(tzNO2)2]Ag[P(m-tol)3]2} (2) _________________________________ 114
3. Results and discussion _________________________________________________________________________ 115
3.1. Syntheses _______________________________________________________________________________ 115
3.2. Spectroscopy ____________________________________________________________________________ 116
3.3. X-ray crystallography ______________________________________________________________________ 119
Chapter 8
Silver(I)-organophosphane complexes of a highly electron withdrawing nitro-substituted scorpionate ligand _______ 121
1. Experimental ________________________________________________________________________________ 121
1.1. Materials and general methods _______________________________________________________________ 121
1.2. Synthesis of the ligand _____________________________________________________________________ 122
1.3. Syntheses of Silver complexes _______________________________________________________________ 123
1.4. X-ray data collection and structure determinations _______________________________________________ 125
2. Results and discussion _________________________________________________________________________ 126
2.1. Syntheses, consideration and general characterization _____________________________________________ 126
2.2. X-ray crystal structural data _________________________________________________________________ 130
3. Summary and conclusion ____________________________________________________________________ 132
Chapter 9
Synthesis, Characterization, and in Vitro Antitumor Properties of Tris(hydroxymethyl)phosphine Copper(I) Complexes
Containing the New Bis(1,2,4-triazol-1-yl)acetate Ligand _________________________________________________ 133
1. Experimental ________________________________________________________________________________ 134
1.1. Materials and general methods _______________________________________________________________ 134
1.2. Syntheses. _______________________________________________________________________________ 134
1.3. Na[HC(CO2)(tz)2] (1) ______________________________________________________________________ 135
1.4. [HC(CO2)(tz)2]Cu[P(CH2OH)3]2 (2) __________________________________________________________ 135
1.5. [HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2 (3) ________________________________________________________ 136
1.6. [(CH3CN)2Cu(P(CH2OH)3)2]PF6 (4) __________________________________________________________ 136
2. Experiments with human cells ___________________________________________________________________ 136
2.1. Cell Cultures_____________________________________________________________________________ 137
2.2. Cytotoxicity assay ________________________________________________________________________ 137
2.3. Flow cytometric analysis ___________________________________________________________________ 138
2.4. Caspase-3 activity ________________________________________________________________________ 138
3. Results and Discussion ________________________________________________________________________ 138
3.1. Syntheses and characterization of Cu(I) complexes _______________________________________________ 138
3.2. Cytotoxicity studies _______________________________________________________________________ 142
3.3. Cell cycle and apoptosis studies ______________________________________________________________ 144
Chapter 10
New triorganotin(IV) complexes of a polyfunctional S,N,O-ligand _________________________________________ 148
1. Experimental ________________________________________________________________________________ 149
1.1. General _________________________________________________________________________________ 149
1.2. Synthesis of [(pyS)2CHCO2]Na (1) ___________________________________________________________ 150
1.3. {[(pyS)2CHCO2]Sn(CH3)3}n (2) ______________________________________________________________ 151
1.4. {[(pyS)2CHCO2]Sn(C4H9)3} (3) ______________________________________________________________ 151
1.5. {[(pyS)2CHCO2]Sn(C6H11)3} (4) _____________________________________________________________ 152
1.6. {[(pyS)2CHCO2]Sn(C6H5)3} (5) ______________________________________________________________ 152
1.7. X-ray crystallography ______________________________________________________________________ 153
2. Results and discussion _________________________________________________________________________ 153
References __________________________________________________________________________________ 157
4
Chapter 1
Introduction
1. Polypyrazolylborate and Scorpionate Ligands
Since the first report of Trofimenko,1 many papers have appeared describing the synthesis and the
application of poly(pyrazolyl)borates, or Trofimenko ligands, in an extraordinarily wide range of
chemistry, from modeling the active site of metallo-enzymes, through analytical chemistry and organic
synthesis, to catalysis and material science.
R'
R
E
N N
N
M
N
Fig.1.
After the early reviews in 19712 and 19723 on poly(pyrazolyl)borate chemistry and pyrazole derived
ligands, and the boron–pyrazole compounds chemistry described in 1986,4 Trofimenko reported in
19865 and in 19936 a summary on the coordination chemistry of poly(pyrazolyl)borates. In 1999
Trofimenko described the coordination chemistry of scorpionate ligands in a book.7
Apart from Trofimenko’s reviews, a number of reviews and chapters were devoted to this subject:
Shaver8 wrote a chapter on poly(pyrazolyl)borate and related ligands; in 1983 McCleverty reviewed his
work on chemistry of Tp* with Mo and W;9 in 1988 Niedenzu reviewed the pyrazaboles;10 in 1992
5
Canty wrote about the simple tris(pyrazolyl)borato chemistry of Pd and Pt.11 In 1995 Santos and
Marques discussed coordination chemistry of tris(pyrazolyl)borate ligands in lanthanides and actinides
complexes; in the same year Parkin reported metal hydroxides, hydrides and organometallics derived
from hindered poly(pyrazolyl)borate ligands,12 while Kitajima and Tolman reviewed the
organometallic and bioinorganic chemistry of hindered Tpx ligands.13 In 1996 Etienne devoted a review
to the coordination chemistry of Tp ligands with V, Nb, and Ta14 and in 1997 and 1998 Janiak
summarized the coordination chemistry of Tpx toward Tl.15 In 1998 McCleverty and Ward described
the use of scorpionate ligands to form a variety of bridged polynuclear complexes of Mo;16 the same
authors reviewed their work on coordination and supramolecular chemistry of TpPy-based ligand in
2001.17 Vahrenkamp recently reported the zinc pyrazolylborate chemistry related to zinc enzymes. 18 In
2001 Slugovc and Carmona described C–H activation and coordination chemistry of rhodium– and
iridium–tris(pyrazolyl)borate complexes.19
The fundamental feature in all poly(pyrazolyl)borate complexes is the six-membered ring within a
more general structure RR’B(-pz)2M(L)n, (1).
(1)
Because of the bond angles and distances involved, the B(-pz)2M ring has nearly a boat conformation.
In Structure (1) R and R’ are different: the pseudoequatorial R’ is pointing away from the metal
roughly along the B–M axis, but the pseudoaxial R is directed towards the metal, and may bond to it,
interact with it, or simply screen it from other ligands. R may be H, alkyl, aryl, OR, SR, NMe2, or
another pyrazolyl group with unspecified substituents (pzx). It was this feature that prompted
Trofimenko to coin the term ‘‘scorpionates’’ for poly(pyrazolyl)borates, as the coordination behavior
of the RR0’B(-pz)2 ligands closely resembles the hunting habits of a scorpion (Fig. 1): this creature
6
grabs its prey with two identical claws (coordination of M through the two 2-N atoms of the B(-pz)2,
groups), and then may, or may not, proceed to sting it with its overarching tail (the R’ group).
Two families of scorpionate ligand may be distinguished. The first is homoscorpionates, where the
pseudoaxial R group is another pyrazolyl group (pzx) identical to the two bridging pzx groups. In this
case the ligand is tridentate and has local C3v symmetry. Homoscorpionates typically coordinate to the
metal in a tridentate fashion, a feature that prompted a comparison of the Tp ligands system with the
cyclopentadienyls Cp or Cpx. The second family are the heteroscorpionates, where the coordinating
pseudoaxial R group is anything but pzx. Heteroscorpionates also include ligands where R is another
pyrazolyl group (pzy) different from pzx. Heteroscorpionate ligands may coordinate in a tridentate
fashion, not only in the case the where R is pzy or a heteroatom, but even in cases where R is a
hydrogen or an alkyl group (agostic bonding).
1.1.
Abbreviation System
The systematic method to represent tris(pyrazolyl)borate ligands, proposed by Curtis, 20,21 is to use the
abbreviation Tp for the hydrotris(pyrazol-1-yl)borate (also indicated as HB(pz)3) and Tp* for
hydrotris(3,5-dimethylpyrazol-1-yl)borate (also indicated as HB(3,5-Me2pz)3). For the sake of
convenience we adopt here the Tp nomenclature. The tetrakis(pyrazol-1-yl)borate ligand will be
represented by pzTp and the dihydrobis(pyrazol-1-yl)borate ligand by Bp. As proposed by Trofimenko6
other poly(pyrazolyl)borate ligands are identified on the basis on the Tp abbreviation and using the
following rules:
a) The basic HB(pz)3 structure is denoted by Tp, and a non-hydrogen substituent in the 3-position is
denoted by a superscript. Thus, hydrotris(3-methylpyrazol-1-yl)borate is denoted as TpMe and
hydrotris(3-phenylpyrazol-1-yl)borate TpPh, and so forth. This is because in the reaction of KBH4
with 3(5)-monosubstituted pyrazoles the asymmetric R-substituent ends up in the 3-position of the
ligand. When there are four identical pyrazolyl groups bound to boron, as in tetrakis(3methylpyrazol-1-yl)borate, the ligand will be denoted as pzTpR. Boron substituents are written
preceding ‘‘Tp’’: for instance, butylhydrotris(pyrazol-1-yl)borate is BuTp.
b) The 5-substituent follows the 3-substituent as a superscript, separated by a comma. For instance,
hydrotris(3-isopropyl-5-methylpyrazol-1-yl)borate is denoted as TpiPr,Me. When both 3 and the 5
substituents are identical, the superscript R-substituent is followed by a 2: for instance
hydrotris(3,5-diisopropylpyrazol-1-yl)borate is TpiPr2. In the case of the most commonly used
7
ligand, hydrotris(3,5-dimethylpyrazol-1-yl)borate the systematic abbreviation would be TpMe2
although, considering the long historical use of Tp*.
c) A substituent in the 4-position is denoted as a 4R superscript. Thus, hydrotris(3-methyl- 4bromopyrazol-1-yl)borate is TpMe,4Br and hydrotris(4-chloropyrazol-1-yl)borate is Tp4Cl. Since
Tp* defines uniquely the position of the two methyl substituents, a substituent in the 4-position
follows the asterisk: for instance, the hydrotris(3,4,5-trimethylpylpyrazol-1-yl)borate ligand is
Tp*Me.
d) Poly(indazolyl)borates ligands will be represented as benzopyrazolylborates, TpBo, with the mode
of fusion of the benzo ring to pz indicated by the superscript of 3 or 4 preceding ‘‘Bo’’ to indicate a
3,4- or 4-5 fusion of the benzo ring, and with the position numbering following the indazole
numbering system.
e) A general homoscorpionate ligand with unspecified substituents will be denoted as Tpx, and a
general pyrazolyl group will be pzx.
f) Heteroscorpionate ligands will be abbreviated as ‘‘Bp’’, with the C-substituents denoted as defined
above for Tp, and with the non-hydrogen substituents on the boron written before the abbreviation.
For instance, diethylbis(pyrazol-1-yl)borate will be denoted as Et2Bp, and dihydrobis(3tertbutylpyrazol-1-yl)borate as BptBu.
1.2.
Preparation of poly(pyrazolyl)borates
Poly(pyrazolyl)borate ligands are prepared, through a more general reaction, by heating
tetrahydroborate ion in molten pyrazole (Scheme 1):
Scheme 1
This reaction can be stopped, through careful temperature control, to yield bis-, tris-, and in the case of
5-unsubstituted pyrazoles, tetrakis(pyrazolyl)borates. Syntheses of the parent ligands Bp, Tp, and pzTp
have been described in detail.22 A large variety of 1-H pyrazoles may be employed to synthesize
8
poly(pyrazolyl)borate by this route, with the exception of those containing functionalities incompatible
with the borohydride ion.
A substituent in the 3-position of a Tp ligand has the most telling effect on the coordination chemistry
of the resulting Tpx ligand. This is because the 3-substituent is closest to the coordinated metal ion, and
it defines the size of the cavity harbouring the metal, as expressed by cone and wedge angles, or by
some other means. The effect of a 3-substituent is dominant, and any additional substitution at the 4- or
5-positions, while at times of some significance is of secondary importance. The 4-substituent on the
pyrazolyl ring is remote from both coordinated metal and boron atom, being thus of little steric
consequence. However, the 4-substituents may influence the electron density of the ligand through
electron donation or withdrawal. Two types of 3,4-disubstituted Tpx ligands are known: the first is
derived from a 3-substituted pyrazole, which was additionally substituted in the 4-position either by
halogenation, which is very facile with pyrazoles, or by the introduction of an alkyl group which is
more difficult; the second contains a fused benzo-, or naphtho-ring at the 3,4-positions of the pyrazole,
that is, the Tpx ligands are hydrotris(indazol-2-yl)borates. The examples known are limited to ligands
derived from indazoles that contain either a 7-alkyl substituent, or a 6,7-fused benzo ring. There are a
variety of known 3,4,5-trisubstituted Tpx ligands. The most common trisubstituted ligands are derived
from Tp*, where a halogen or an alkyl group was introduced into the 4-position. In general,
substituents in the 4-position do not introduce major deviations from the coordination chemistry of the
Tp* ligands.
Tetrakis(pyrazolyl)borate ligands, pzTpx, which are limited to 5-unsubstituted pyrazoles, are prepared
by the reaction of Hpzx with KBH4 in a 5–6:1 mol ratio. After completion of the reaction, excess Hpzx
is either distilled off, or sublimed in vacuo, and the residue can be directly used for the synthesis of
complexes or it can be converted to the Tl salt.
The boron-substituted ligands, RTpx, where R is alkyl or aryl, are generally prepared from the reaction
of RBX2 or ArBX225,26 (X = halogen or a leaving group such as tosylate) with the
pyrazolate ion and excess pyrazole (Equation (1)).
RBX2 + 3[pzx]- → [RB(pzx)3]- + 2X-
(1)
Alternatively, the [RB(pzx)3]- ligands may be prepared from the reaction of alkyl or arylboronic
acids,23,24 or RB(OR)2 ester,25-27 with the pyrazolate ion and excess pyrazole (Equation (2)).
9
RB(OH)2 + [pzx]- + 2Hpzx → [RB(pzx)3]- + 2H2O
(2)
A different route employs organoborohydrides RBH2 or LiRBH3,28 obtained from the reaction of the
corresponding boronic acids RB(OH)2 with LiAlH4,29 in the reaction with pyrazolate ion and excess
pyrazole (Equation (3)).30
RBH2 + [pzx]- + 2Hpzx → [RB(pzx)3]- + 2H2
(3)
R2Bpx type ligands are prepared from trialkylboranes, triarylboranes, or tetraphenylborate ion. A
typical reaction of an R3B or Ar3B species with pyrazole is preceded by the formation of an anionic
species [R3Bpzx]-, through the reaction of R3B with a pyrazolate ion, [pzx]-. The R group in [R3Bpzx]can be replaced by a pzx group upon reaction with excess pyrazole (Equation (4)).
R3B + [pzx]- → [RB(pzx)3]- + RH
(4)
The presence of sufficient pyrazolate ion (pz)- is necessary to convert the R2B(pzx) species quickly to
the [R2B(pzx)2]-, otherwise the R2B(pzx) species will dimerize to the stable pyrazabole R2B(–pzx)2BR2
(2), which are not readily convertible to scorpionate ligands.31
The reaction (4) generally stops at the disubstitution stage. With high boiling substituted pyrazoles, it
can be driven one step further to obtain the [RB(pzx)3]- species. As with the KBH4 reaction, the
pyrazole 3(5)-substituent ends up in the 3-position.
(2)
1.3.
Bpx Ligands
Heteroscorpionate ligands can exist in two general structures: The difference between these two
structures is that in (3) there is no interaction of the pseudoaxial R group with the coordinated metal
10
ion, while in (4) there is such an interaction, which can range from a regular bond, through a longdistance bond, to an agostic interaction. All of this depends, of course, on the nature of R, and the depth
of the boat in the B(-pzx)2M ring.
The known types of heteroscorpionate ligands are:
1)
H2B(pzx)2 (or Bpx), including R2B(pzx)2 (or R2Bpx), (5), where R¼alkyl, aryl, or halogen.
2)
R(R'Z)B(pzx)2 ( = R(R'Z)Bpx), where R = H, alkyl, aryl, and Z is a heteroatom (O, S, NR').
3)
H2B(pzx)(pzy) where pzx and pzy are different pyrazolyl groups.
In general, the H2B(pzx)2 ligands are prepared from reaction, in refluxing anhydrous DMF, of
substituted pyrazole and MBH4 (M = Li, Na or K) in a 2.3:1.0 mole ratio. When the reaction is
complete, DMF is distilled out at reduced pressure. The residue is boiled with toluene, which should
dissolve most of the un-reacted pyrazole, and the mixture is filtered. The crude M[H2B(pzx)2] is
contaminated by only small amounts of Hpzx and is usually suitable for complex formation. Additional
purification can be achieved by converting the crude K salt to the Tl salt which shows no tendency to
retain Hpzx.
11
1.3.1. Specific Bpx Ligands
Bpx ligands are characterized by the presence of the BH2 group which, although it renders the Bpx
ligands more hydrolytically labile than their Tpx counterparts, permits elaboration of the Bpx ligand
through the addition of various unsaturated systems to the B—H bond. Moreover the Bpx ligands are
able to establish an agostic B—H—M bond with many metals. Finally, the residual reducing power of
the BH2 group makes the Bpx complexes of easily reducible cations, such as silver(I) and palladium(II),
unstable, and they can be used in some instances for organic reductions.
The Bp ligand is the simplest of all heteroscorpionate ligands, and it is basically bidentate, forming the
typical boat-shaped H2B(-pz)2M ring, in which the pseudoaxial B—H may sometimes form an agostic
bond with the metal.32,33 Bp2M complexes of first-row transition metals are usually square planar or
tetrahedral,34 although some octahedral anionic [Bp3M]- species of low stability can be isolated.35,36
Five-coordinate anionic species [Bp2MX]- (M = Cr, Mn; X = halides or pseudoalides) have also been
prepared
and
characterized.37,38
Stable
2-iminoacyl-carbonyl
derivatives,
BpMo(2
RN=CBut)(CO)2(PMe3),39,40 are reported and a brief review on the structural and reactivity aspects of
molybdenum acyl complexes derived from the Bp and Bp* was published.41 A large number of
octahedral complexes of the BpRu moiety have been prepared; they included BpRu(R)(CO)(PPh3)2 and
BpRu(R)(CS)(PPh3)2 (R = H, Ph and vinylic).42 Acetyl complexes of Fe and Ru, such as
BpM(PMe3)2(CO)(COMe), were also reported.43 Syntheses of numerous palladium complexes,
BpPd(PMe3)(R), have been reported, (R = CH2CMe2Ph, CH2SiMe3).44 BpCu was synthesized and
converted to derivatives of general structure BpCuL (L = bipy, dppe, (py)2, (PPh3)2 and PCy3). BpCu is
able to catalyze the cyclopropanation of olefins with diazoacetic ester in homogeneous and
heterogeneous systems.45 Gallium and indium complexes of Bp were reported including Bp2GaCl,
Bp3Ga, Bp2GaMe and BpGaMe2.46 A number of other related indium(III) complexes (BpInMeCl and
BpInMe2) were also reported.47 Bp2Sn and (BpSnCl)2 have been synthesized, and the structure of the
latter showed a long-range halide interaction between the two tin ions, which were in a pyramidal
environment.48,49 Several tin(IV) complexes BpSnClR2 and Bp2SnR2 (R = Me, Bu, Ph) have been
described47 showing that halogenation of BH2 moiety occurs without ligand degradation. Five- and sixcoordinate organotin(IV) complexes, BpSnClMe250 and BpSnClR251 R:CH3OOCH2CH2 respectively,
were also described.
Various Bp*2M (M = first-row transition metal) were synthesized and found to resemble their Bp2M
counterparts, with the exception of Bp*2Mn and Bp*2Fe these complexes are no longer airsensitive,
presumably due to the screening effect of the 3-Me groups. In recent years a variety of
12
Bp*Pd(PMe3)(R) complexes has been reported, and the structure of Bp*Pd(PMe3)(CH2SiMe3) was
determined by X-ray crystallography. Several gallium(III) and indium(III) complexes of Bp*, including
Bp*M(Me)Cl and Bp*M(Me)2 have also been described.52 Bp* complexes of lanthanides and actinides
were synthesized, and structures of the isomorphous Bp*3U and Bp*3Sm determined by X-ray
crystallography. The same structural typology was found in Bp*3Y.53 In these complexes the Bp*
ligand is tridentate, by way of a B—H—M agostic bond, so that the metal ions were in a formally ninecoordinate environment, and the six nitrogen atoms were arranged in a trigonal prismatic geometry.
In 1982 the first Bpx ligand containing two different pyrazolyl groups, [H2B(pz)(pz*)]-, was
synthesized;54 this was converted in the sodium salt [H2B(pz*)(pzx)]Na.55 The nickel complex
[H2B(pz)(pz*)]2Ni was synthesized and the structure determined by X-ray crystallography showing a
square planar structure containing the (pz) and (pz*) rings in a trans arrangement.56 The asymmetric
ligands, [H2B(pz)(pztBu2)]-, [H2B(pz*)(pztBu2)]- and [H2B(pztrip)(pztBu2)]-, were obtained by reaction of
LiBH4 with a 1:1 mixture of two different pyrazoles and their thallium complexes [H2B(pz)(pztBu2)]Tl,
containing an agostic B—H—Tl bond, were structurally characterized together with the zinc
derivatives ([H2B(pz)(pztBu2)]ZnI(HpztBu,iPr), [H2B(pz*)(pztBu2)]ZnI and [H2B(pztrip)(pztBu2)]ZnI (6).57 In
the latter case the zinc ion was in a tetrahedral environment, due to the presence of an agostic B-H-Zn
bond.
(6)
The BpMe ligand was synthesized in 197558 and converted to a variety of first-row transition metal
complexes56 and tin(II) complexes.49 In a similar way the BpPh ligand was isolated as a thallium(I) salt,
and was converted to first-row transition metal complexes (BpPh)2M, as well as to BpPhMO(CO)2(3CH2CRCH2) (R = H, Me).59
The more sterically hindered BpiPr and BptBu ligands were synthesized and characterized respectively as
potassium60 and thallium59 salts. Several three-coordinate monoalkylzinc derivatives BptBuZnR (R =
13
Me, Et, But) were prepared,61 as well as a number of nickel complexes BptBuNi(Ar)(PMe3)2 (Ar = Ph,
Tol, An, Ph-p-NMe2), containing a very rare example of a monodentate BptBu ligand.62 The BptBu,iPr
ligand was synthesized. Its cobalt complex [BptBu,iPr]2Co, is in an octahedral environment, due to the
presence of an agostic B-H-Co bond.63 The organozinc complex of this ligand, [BptBu,iPr]ZnMe, was
converted by treatment with paraformaldehyde to [(MeO)BptBu,iPr]ZnMe, which involved insertion of
CH2O into the pseudoaxial B—H bond.64 The K salt of the fluorinated Bp(CF3)2 was synthesized,65,66
and the structure determined by X-ray crystallography as was the square planar [Bp(CF3)2]2Cu complex,
and the tetrahedral [Bp(CF3)2]2Zn.67 The copper(I) complex [Bp(CF3)2]Cu(CNBut)2, showing an agostic
B—H—Cu bond, was also characterized.68 An analogous agostic interaction was present in the
ruthenium complex [Bp(CF3)2]RuH(COD), which was converted to [Bp(CF3)2]RuH(PR3)3 and
[Bp(CF3)2]RuH(C6H6), in which no agostic B—H—Ru bond is present, and to [Bp(CF3)2]RuH(H2)(PCy3)2
where [Bp(CF3)2] is coordinated in the rare monodentate mode.69
The potentially tetradentate bis(pyrazolyl)borate ligand BpPy with two bidentate arms (7), was
prepared from reaction of 3-(2-pyridyl)pyrazole (Hpzpy) with KBH4 in a melt.70
(7)
The coordination properties of the ligand BpPy can be split into two categories: i) all donor atoms
coordinate to the same metal ion, to give in this case a tetradentate chelate; ii) the two bidentate arms
attach to different metal ions, in which case more elaborate polynuclear complexes may assemble. The
simple mononucleating coordination mode of BpPy is exemplified by the structures of Tl(BpPy) and
Ln(BpPy)2(NO3). In Tl(BpPy) the Tl(I) ion has two short strong interactions with the pyrazolyl N donors
(between 2.61A and 2.69A), and two much more tenuous ones with the pyridyl N donors (between
2.96A and 3.17A).71 In Ln(BpPy)2(NO3) the two BpPy ligands are coordinated as conventional
tetradentate chelates, with the lanthanide ion being ten-coordinate from two such ligands and a
bidentate nitrate.72 Reaction of BpPy with Co(II) salts, followed by precipitation with
14
hexafluorophosphate as the anion, afforded a material whose electrospray mass spectrum contains a
peak corresponding to the fragment [Co8(BpPy)12(PF6)]3+ at m/z 1410.73 The crystal structure of the
perchlorate salt shows the eight metal ions and twelve bridging ligands form a closed ring, with the
perchlorate ion bound in the centre of the cavity. Each ligand BpPy acts as a bridge between two
adjacent metal ions, with an alternating pattern of one and two bridging ligands between each adjacent
pair of metals. Each metal is therefore six-coordinate (pseudo-octahedral) by three bidentate chelating
fragments, each from a different ligand. BpPyTl and BpPy2Pb were also reported. The BpPyTl structure
revealed molecular stacking, with two long bonds from the pyridyl nitrogen atoms to Tl, while in
BpPy2Pb all eight nitrogen atoms were directed at the metal ion, with variable degrees of interaction.71
The potentially hexadentate ligand, BpBipy (8) was synthesized and the structure of its K salt was
determined by X-ray crystallography.74
(8)
The first-row ions yielded dinuclear cationic complexes [(BpBipy)2M]2[BF4]. The structure of the
complex [(BpBipy)2Cu]2[BF4]2 revealed a double helical ligand array, which also included stacking
between ligands, while [BpBipy]Gd(NO3)2 showed a hexadentate BpBipy ligand with two 2 nitrate ions.
In BpBipyTl the metal is three-coordinate.75
1.4.
Tpx Ligands
In general, the procedure for the synthesis of Tpx ligands involves thermolysis of a mixture of a suitable
pyrazole and a borohydride salt, MBH4 (M = K or Na), in a 4:1 ratio, either in a melt or in a highboiling solvent. The reaction was monitored by hydrogen evolution. When the pyrazole is a liquid or a
low-melting solid, the excess pyrazole is distilled out keeping the temperature as low as possible, in
15
order to prevent the formation of the tetrasubstituted pzTpx ligand. The residual M[Tpx] salt can be
converted to the Tl(I) salt and purified by recrystallization.
If the pyrazole is 3-substituted and high-melting, the best method is to reflux a mixture in 3.5:1 pzx to
MBH4 ratio in a high-boiling solvent such as toluene, anisole, methylanisole or kerosene. As with
pyrazole itself, the reactions affording Tpx ligands proceed via the dihydrobis (pyrazolyl)borate anion,
which in some instances was isolated.59 If the temperature is too high the pzTpx anion can also be
isolated. When large R groups are in the 3-position the formation of the more highly boron-substituted
product is relatively disfavored, facilitating the preparation of the desired Tpx in most cases. If it
precipitates, the mixture is filtered hot, and the solid is washed with a small amount of hot solvent
itself. After drying, a very pure MTpx salt is usually obtained. If the theoretical amount of hydrogen
evolves and the solution remains clear, then the solvent is distilled out under vacuum and the residue is
converted to the thallium salt by treatment with aqueous TlNO3 or methanolic TlOAc. In order to
obtain the ligands in a pure form the thallium salt is extracted with methylene chloride, and the extracts
are filtered, stripped and stirred with methanol in which Hpzx, but not TlTpx, is usually soluble.
With 3,5-disubstituted pyrazole the melt method is preferred, since tetrasubstitution does not take
place, and high temperatures can be employed. It would be better to use a large excess of Hpzx
(Hpzx:MBH4 in 6:1 molar ratio) to prevent the precipitation of the less soluble potassium or sodium
salt and decomposition. After completion of the reaction, the excess of Hpz x is sublimed out and the
residue is converted to the TlI salt in the usual way.
1.4.1. Regiochemistry in ligand synthesis
A critical issue in the synthesis of polypyrazolylborate ligand obtained from pyrazoles whose anions
are not of C2v symmetry, is the regiochemistry of B—N bond formation. Usually, the larger
substituents end up in the pyrazolyl ring 3-position, relatively distant from the B—N bond. This
tendency is most pronounced when the steric differences between R(3) and R(5) are large. This
regioselectivity was first demonstrated in the reaction of 3(5)-methylpyrazole, leading to BpMe and to
TpMe
76
as well as in the regiospecific synthesis of TpPh
77
and TptBu.59 A mixture of TpR and Tp5R
isomers is often formed when the steric differences between the pyrazolyl rings substituent in the 3position and in the 5-position are less substantial. For example, reaction of 3-isopropyl-5methylpyrazole with KBH4 resulted in the formation of an approximate 4:1 ratio of TpiPr,Me and its
isomer [HB(3-isopropyl-5-methylpyrazolyl)2(3-methyl-5-isopropylpyrazolyl)]- (= Tp(iPr,Me)*; the
asterisk indicates the isomeric species).78
16
The probable reason for this regioselectivity is that boron–nitrogen bond formation, involving a
concerted loss of hydrogen, proceeds through a less sterically encumbered transition state, when
bonding occurs to the less bindered N(1) rather than to N(2). The only exception is benzopyrazole
(indazole) and its derivatives containing alkyl or aryl substituents in the 3-, 4-, 5-, or 6-positions, which
produces scorpionate ligands where boron is bonded to the more hindered nitrogen. This happens,
presumably, because electronic effects outweigh steric ones. This tendency is most clearly manifested
in
TpCF3,Me 79
and TpCF3,Tn
80
in which electronically quite different substituents are present. The
syntheses of these ligands are highly regioselective, with the larger CF3 group residing exclusively in
the 3-position. The preference of an electron-withdrawing group for the 3-position in Tpx ligands can
be explained to consider that the inductive electron-withdrawing effect of the CF3 group makes the
distal nitrogen more basic, favoring the tautomer with the CF3 group in the 3 position, Hpz3CF3.81 The
relative influence of steric and electronic effects on the course of ligand synthesis is evident from the
preparation of TpMs
82
(HpzMs = 3-mesitylpyrazole) in which the asymmetric isomer [HB(3-Rpz)2(5-
Rpz)]- (= TpMs*) was the major product. A similar situation occurs, for instance, in the synthesis of
TpNp (HpzNp = 3-neopentylpyrazole)83 and TpAnt (Ant = 3(9-anthryl)pyrazole).84
Sometimes a regiochemically pure ligand TpR undergoes rearrangement to TpR* during the course of
complex formation. For example, the 3-isopropyl substituent, in TpiPr and TpiPr,4Br, is large enough to
prevent Tp2M formation, although octahedral cobalt(II) complexes will form if a borotropic migration
occurs in the original ligands to yield TpiPr* and Tp(iPr,4Br)* respectively.60 Octahedral (TpNp)2Ni and
(TpNp)2Co complexes have been isolated and crystallographically characterized. They are
thermodynamically unstable and were converted upon heating to (TpNp*)2Ni and (TpNp*)2Co via a 1,2borotropic shift. Similar rearrangments were also found in the conversion from TptBuAlR2 to
TptBu*AlR2,61,85 from [(TpPh)2Al]+ to [(TpPh*)2Al]+
86
and from TpMenthTiCl3 to TpMenth*TiCl3.87
TpMeIr(COD) was found to rearrange in solution first to TpMe*Ir(COD) and then, on heating, to [HB(5Mepz)2(3-Mepz)]Ir (COD).88
1.4.2. Steric effects
In a M[Tpx] fragment the x substituents protrude in space past the metal, enveloping it, and forming a
protective pocket of varying size and shape. Then, evaluation of the size of the variously substituted
Tpx ligands is more important to develop an understanding of the influence of the pyrazolyl ring
substituents on the chemistry of their metal complexes. Ligand size can be evaluated by the concept of
cone angle (). Refinements to the original method of cone angle determination, which was originally
17
introduced for phosphine ligands,89 which attempt to take into account steric demand changes
accompanying orientational variations have been introduced. The smaller the cone angle, and the larger
the wedge angle, the easier it is for other ligands to coordinate to the metal. Because of this feature, the
proper choice of 3-R substituents does adjust the steric accessibility of the coordinated metal, in this
fashion controlling the coordination chemistry of the TpxM species. Trofimenko and co-workers
calculated cone angles for several Tpx ligands using the dimensions established by X-ray
crystallography for selected complexes,90-92 connecting the center of the metal atom to the outermost
point of the R-group and taking into account its van der Waals radii for all hydrogen atoms.93
All of the Tp ligands have a cone angle () larger then 180°, and the trends in the values of these angles
were consistent with the trends in the coordination chemistry of the Tpx ligands. Indeed, the ligands of
small cone angle (Tp, TpMe, Tpcpr, TpTn) are characterized by a strong tendency to form Tpx2M
complexes with divalent first-row transition metals, and an inability to form stable TpxMX species.94,95
Ligands having an intermediate cone angle (TpiPr, TpiPr2, TpiPr,4Br, TpiPr,Me, TpMenth, TpNp, TpPh and TpAr,
where Ar is a number of various substituted phenyl groups) are able to form both, Tpx2M and TpxMX
species. Indeed, coordination of a solvent (sol) molecule or stronger binding of an additional TpM unit
to form five-coordinate TpMX(sol) or TpM(-L)nMTp dimers, respectively, are possible.
Representative examples of these motifs are the structures of TpiPr2CuCl(dmf), (dmf = N,Ndimethylformamide), [(TpiPr2Cu)2(-OH)(-N3)] and [(TpiPr,4BrNi)2(-NCS)2].96-98
The most sterically demanding ligands (i.e., TptBu, TptBu,Me, TptBu,Tn, TptBu,iPr, TpMs, TpAnt and TpTrip)
inhibit formation of Tp2M and TpM(-L)MTp (L = bridging group) complexes and heavily favor fourcoordinate compounds TpxMX with C3v-distorted tetrahedral geometries. A wide range of structurally
characterized complexes of divalent metal halides and pseudohalides exemplifies these characteristic
features. Representative cases are: TptBu,MeNi(NCS),98 TptBuCuCl.94 However, some exceptions to the
‘‘tetrahedral rule’’ are possible. In fact, small co-ligands such as O2-,99 NO2-,100 and NO3-,94 are able to
bind the metal ions in a bidentate fashion to afford essentially five-coordinate complexes, as well as
monodentate binding of two or three co-ligands to yield five- or six-coordinate complexes,
respectively, of second-row transition metals and lanthanides.101
The cone angles depend not only on the ligand itself, but also on the length of the N—M bond. The
choice of thallium complexes TpxTl, the structures of which have been established by X-ray
crystallography,102,103 as ‘‘standard’’ systems for calculating the cone angles seemed to be the best
choice. These specifications can be used to establish a relative steric hierarchy for the various Tpx
ligands.
18
Comparisons of structures, physical properties, and reactivity of sets of similar compounds with
homologous ligands provide additional insight into the steric demands of the variously substituted Tpx
ligands. For example, it is interesting to compare the X-ray crystal structures of the dimers [TptBuCu]2,
[TptBu,MeCu]2, [TpPh2Cu]2, [TpMe2Cu]2, [TpCu]2, that are useful starting materials for bioinorganic
modeling studies.104-112 Coordination numbers, geometries, and Cu—N distances within the set vary
smoothly with the size of the ligand substituents. Combined results from experimental studies in which
structures, spectroscopic properties, and reactivity of a number of metal complexes were examined,14
can be summarized by the following series in accordance with the effective steric bulk at a complexed
metal center:
TptBu > TpMenth ~ TpiPr ~ TpNp ~ TpMs ~ TpAnt > TpPh ~ TpTol ~ TppAn ~ TppClPh > TpCF3,R > TpMe > TpTn
Ligands with identical R(3) groups but different R(4) or R(5) substituents should probably be placed in
the same category as their analogs with R(4) = R(5) = H, although some structural and spectroscopic
data suggest that their effective size is slightly larger.
1.4.3. Electronic effects
Comparison of the structure, physical and spectroscopic properties of similar compounds with
homologous ligands provide insight into the relative electron-donating or -withdrawing capabilities of
Tpx ligands. Much of these experimental data were collected during efforts to compare Tp and Tp*
ligands with their formally iso-electronic analogs Cp and Cp*. A useful set of molecules to contemplate
are the CpxM(CO)3 and TpxM(CO)3 radicals and anions, where M is Cr, Mo and W.113-115
Stereoelectronic effect differences have been inferred from IR (CO) values and oxidation potentials
for the carbonyl anions.116 The lower oxidation potentials (>0.1 V) and the 15–20 cm-1 lower energy of
the E symmetry (CO) bands for the Tp versus the Cp complexes suggest that the Tp ligand is the
stronger electron donor. Substitution of Tp* for Tp results in shifts of oxidation potentials and of (CO)
bands of the anions to lower values. These data, combined with redox potential measurements acquired
for other complexes, including CpRuTp and CpRuTp* and the set Cp2Fe, Cp*Fe, and Tp2Fe, support
the following trend in ligand electron-releasing capability: Tp*>Tp~ Cp*>Cp.117,118
As recently reported by Kitajima and Tolman, the relative electron-donating or electronreleasing
properties of the more hindered Tpx ligands can be gained by comparing (CO) data for sets of like
metal carbonyl complexes that differ only in their pyrazolyl ring substituents; for example: TpxCu(CO),
19
2-TpxRh(CO)2, 3-TpxRh(CO)2, [NEt4][TpW(CO)3], and TpxMo(CO)2(NO).78,119-121 Higher values for
the carbonyl stretching frequencies reflect lower electron density at the metal center and decreased
electron donation by the Tpx ligand for compounds within each set. Experimental data support the
following trend of electron-donating ability of Tpx ligands:
TpR2 (R = alkyl) > TptBu ~ TpiPr ~ TpMe ~ TpMs > Tp > TpPh2 ~ TpPh > TpCF3,Tn > TpiPr,4Br > TpCF3,Me
The order is generally that expected on the basis of the extensive knowledge of electronic effects of
substituents in organic chemistry; in fact, the electron donation increases with the number of pyrazolyl
alkyl substituents.
1.4.4. Coordination modes
Poly(pyrazolyl)borate ligands are so popular due to their reliability and accountability as spectator
ligands, which normally do not interfere with the reaction scenarios occurring at the metal centers.
Tris(pyrazolyl)borates, Tpx, generally coordinate as tridentate ligands through three nitrogen atoms of
the pyrazole rings 3-N,N’,N’’, (9) thereby providing effective steric shielding of the metal center.
(9)
By introducing suitable substituents (e.g., Me, CF3, tBu, Ph) in the 3-position of the pyrazolyl rings this
effect can be tuned to a large extent. Cone angles much larger than 180° can be achieved with the use
of such sterically demanding scorpionate ligands, which, for example, have been utilized to realize
unusual bonding.
Besides the very common 3-N,N’,N’’ coordination mode, the tridentate 3-N,N’,B-H type (10)110, the
bidentate 2-N,N’ (11)122-124 and 2-N,B-H coordination (12)125-127 are also known. In contrast to the
relatively easy formation of agostic B—H—M bonds with Bpx ligands, the formation of agnostic B—
C—H—M (13) bonds does not occur very frequently. In addition these bonds can easily be broken by
20
donor ligands. At the same time, the R groups may shield effectively the coordinated metal from other
ligands. On the other hand, no agostic interaction was found with the Ph2Bp ligand. Ligands of type
R(Z)Bpx are generally tridentate, due to the presence of a heteroatom Z which can, and does,
coordinate to the metal (14). The [R(Z)Bpx]- ligands will also include those where Z is a pyrazolyl
group, provided it is different from pzx, and is not its regioisomer. It will not include Tpx* ligands,
arising from a rearrangement of a Tpx ligand. Lower denticity, such as 1-N, has also been reported
(15). Recently, Carmona et al. were able to prove a denticity change in a rhodium pyrazolylborate
system and thereby isolate the first ionic complex containing a 0-Tp* ligand (Tp* serves exclusively
as an uncoordinated counter ion).128,129 It was possible to interconvert Tp*-3N, 2N, 1N, and 0
complexes. The stepwise change in the denticity of pyrazolylborate ligands from 3 to 0 may have
important implications in catalytic uses of Tpx metal complexes. Expansion of Tpx denticity beyond 3
can occur by way of the 3-R substituent containing donor atoms, as in the demonstrably hexadentate
Tppy (16),130,131 or in the potentially hexadentate ligands Tpo-An or Tp2,4(OMe)2Ph.132,133 On the other hand,
tetradenticity was reported in Tpx ligands where R doesn’t contain donor atoms, either by way of
agostic bonding,134 or through cyclometalation taking place at one of the aliphatic R groups per ligand
(17).135 Recently an example was reported of an unusual 5 coordination demonstrated by hydrotris(3phenylpyrazolyl)borate ligands (TpPh) (18).136 Yet another entirely new aspect of scorpionate
coordination chemistry is the 5 coordination of a pyrazole ring. Despite the formal similarities with
the cyclopentadienyl ligands a -interaction between a pyrazolylborate ligand and a metal center was
recently reported only in a blue complex of composition [{(KTpCF3,Me)2(CuCO3)}2] (19).137 Of special
interest is the coordination environment around the potassium center. One of the coordination
hemispheres of the potassium ion is occupied by two carbonate oxygen atoms, one N atom of the
TpCF3,Me ligand, and three fluorine atoms. On the opposite side the potassium ion is located directly
above the center of a pyrazole ring, thus allowing a comparison with the 5-cyclopentadienyl
coordination in polymeric KCp.138
21
22
1.5.
Soft S-donor scorpionates
For the nomenclature of these ligands (Scheme 2) we adopt a scheme derived from that of the
tris(pyrazolyl)borate
ligands.
We
call
the
bis(thioimidazolyl)hydroborate
RBmx
and
the
tris(thiomidazolyl) hydroborate RTmx with x naming the substituent at the 1-positions of the imidazole
rings and R the substituent at boron atom.
Scheme 2
1.5.1. Hydrobis(mercaptoimidazolyl)borates (Bmx)
The bidentate S2-donor bis(mercaptoimidazolyl) ligands BmMe and BmMes were obtained by Parkin by
reaction of LiBH4 with two equivalents of 2-mercapto-1-R-imidazole in toluene at 50 °C. Since
thallium derivatives have proven to be useful reagents for transferring bis- and tris(pyrazolyl)borate
ligands, the thallium complex [BmMe]Tl was prepared by reaction of [(BmMe)Li] with Tl(O2CCMe).139
Subsequent treatment of (BmMe) and (BmMes) with ZnX2 (X = Me, I, NO3) yields a series of
[(Bm)ZnX] complexes each of which possesses 3-center-2-electron [Zn
H–B] interactions (20).
(20)
23
The homoleptic complex [(Bm)2Zn] may be obtained by a redistribution reaction of [(Bm)ZnMe] in
CHCl3, and possesses a tetrahedral zinc center which is devoid of a 3-center- 2-electron [Zn
H–B]
interaction.139 The zinc complexes [(Bm)ZnX] are monomeric in the solid state whereas the Li and Tl
species are oligonuclear with the metal centers being bridged by sulphur atoms of the
mercaptoimidazolyl group. The isolation of the 1:1 [(Bm)ZnX] species provides a contrast with the
homoleptic L2Zn derivatives that have been previously obtained using related S2-donor ligands.
The ligands RBmMe (R = Me and Ph) have been described by Santos who also reported their
coordination chemistry towards U(III) and Re(I) salts.140
Kimblin and Parkin also reported the synthesis and use of pzBmMe to provide [SSN] coordination
environments suitable for modeling aspects of the bioinorganic chemistry of zinc enzymes.141
Complexes [(pzBmMe)2M] (M = Zn, Co or Cd), despite their similar composition, adopt a different
structure: 1) the zinc complex exhibits a tetrahedral Zn[S4] core in which only the sulfur donors
coordinated to metal; 2) the cobalt complex a trigonal–bipyramidal Co[S3NH] structure in which one of
the pyrazolyl groups and one of the BH coordinates to metal; 3) the cadmium complex exhibits a sixcoordinate Cd[S4H2] structure in which both BH interact with the metal. In addition Parkin
demonstrated that the mixed bis(thioimidazolyl)(pyrazolyl)hydroborates open the way to tetrahedral
(N,S,S)Zn–X complexes. It became obvious too, however, that such complexes have a tendency for
dismutation, resulting in neutral bis(ligand) complexes with ZnS4 coordination.
1.5.2. Hydrotris(mercaptoimidazolyl)borates (Bmx)
Reglinski and co-workers have recently reported the synthesis of the tripodal S3-donor TmMe by
reaction of [BH4]- with 2-mercapto(imidazolyl)borato ligands in the melt, a procedure similar to that
used in the preparation of tris(pyrazolyl)borato derivatives.142 Treatment of zinc bromide with excess
ligand leads to the preferential formation of the 1:1 complex [(TmMe)ZnBr] (20).142 In some cases
TmMe offers a slightly different metal binding geometry to that found in Tp, as demonstrated by the
comparison of the [(Tp)ZnBr] with [(Tm)ZnBr]. The ligand TmMe is the first example of a soft, singly
charged, tridentate trigonal six-electron donor analog of Tp. TmMe, along with the mixed
pyrazole/methimazole donor ligand pzBmMe, has great potential for tuning the electron density at the
metal center and hence the redox properties, a factor which is of great importance when exploiting the
coordination chemistry of organometallic compounds in catalysis and material science. This novel
ligand system maintains the tripodal geometry around the boron while allowing the replacement of the
three nitrogen donor atoms by three sulfur thione donor atoms, thus providing a complementary soft,
24
tridentate face capping ligand system. The compound (TmMe)Na is essentially salt like with discrete
anions and hydrated sodium cations.143
Reglinski (TmMe), Parkin (TmPh and TmMes)144, Vahrenkamp (Tmt–Bu and TmCum)145 and Rheingold
(TmBz and Tmp-Tol)146 showed that this family of ligands is indeed suitable for a biomimetic zinc
complex chemistry.
In their initial attempts to prepare classical chelate complexes containing TmMe, Hill and co-workers
have encountered an unprecedented class of reaction for tris(azolyl)borate, namely the intramolecular
activation of the bridgehead B—H bond which provides the first example of a metallaboratrane.147 The
reaction
of
TmMe
with
[Ru(R)ClCOPPh3]
(CH=CHCPh2OH)
likely
yield
the
complex
[Ru(R)(CO)(PPh3)(TmMe)]. In contrast to the rigid chelation of Tp ligands, the more expansive
chelation of (TmMe) might be expected to be more flexible and labile. Dissociation of one (TmMe) arm
followed by agostic BH coordination and ultimate oxidative addition of the BH bond could provide a
cis-hydrido-vinyl complex that undergoes alkene reductive elimination with formation of the complex
(21). The remarkable facility with which the ruthenaboratrane forms may presumably be traced to both
the lability of (TmMe) chelation and the increased ring size of the chelates, which allows the scorpion
sting to more closely approach the metal center.
(21)
The tris(mercaptophenylimidazolyl)borate iron and cobalt complexes [(TmPh)2M] (M = Fe, Co) have
been synthesized by reaction of (TmPh)Tl with MI2.148 Structural characterization by X-ray diffraction
demonstrates that the potentially tridentate TmPh binds through only two sulphur donors in these
sandwich complexes and that the tetrahedral metal centers supplement the bonding by interactions with
two BH groups. Comparison of the structures of [(TmPh)2M] with those of related tris(pyrazolyl)borate
counterparts indicates that the Tm favors lower primary coordination number in divalent metal
complexes.
25
The molecular structure of (TmPh)2Pb, synthesized by Parkin,149 was determined by X-ray diffraction,
revealing that it possesses an unusual structure with an inverted 4-coordination mode for the TmPh
ligand which includes a Pb
H–B interaction. Whereas an inverted 3-coordination mode for the TmMe
ligand was found in a silver(I) phosphino compound.150 In absence of phosphine TmMe reacts with
silver yielding a dinuclear complex in which the S3-donor acts in tetradentate bridging fashion.151 The
same ligand reacts with triorganotin(IV) moieties acting in an unprecedented monodentate S-donor
coordination mode.152
Molybdenum and tungsten complexes containing TmMe are reported as the first examples of transitionmetal organometallic complexes of this family of ligands, serving as general entry points for a wide
range of Group 6 organometallic complexes. The crystal structures have been determined, and
comparison is made with the homologous pyrazolylborate (Tp) and cyclopentadienyl (Cp) complexes,
leading to predictions regarding their reactions.153
1.5.3. Other S3-donor Scorpionates
The synthesis of new soft tripodal anions, hydrotris-(mercaptothiazolyl)borates (Tz) and
(mercaptobenzothiazolyl) borates (Tbz) (Scheme 3) was reported by Ojo using the protocol of
Trofimenko (Scheme 1). Ojo indicated that analysis of the respective thione melting points and pKa
values enables the prediction of which thiazolylborate anions can be produced using borohydride melts.
The X-ray crystal structure of [Tl(Tbz)]ω is also reported.154
Treatment of 5-thioxo-4,5-dihydro-3,4-dimethyl-1,2,4-triazole with sodium tetrahydroborate at 210 °C
provides the new N3S3-donor tripod ligand Tt as its sodium complex salt [Na(H2O)6] [Na(Tt)2]. Bailey
also describes some Tt bismuth(III), tin(IV) and manganese complexes, which illustrated the flexible Tt
offering a combination of the properties ot the Tp and Tm ligands.155
Scheme 3
26
1.6.
Poly(imidazolyl)borates
Poly(imidazolyl)borates HnB(im)4-n (Scheme 4) can be prepared by analogy with that reported for
poly(pyrazolyl)borates.156 HnB(im)4-n can be used to model the histidine imidazole coordination in
metalloproteins. HnB(im)4-n complexes have been widely described,157 but only few metal derivatives
are structurally authenticated: i.e., the ionic lithium salt of tetrakis(imidazolyl)borate,158 a
hydrotris(imidazolyl)borato thallium(I), in which each imidazolyl ring coordinates a different thallium
ion to form a one-dimensional twisted ladder-like strand159 and two silver(I) compounds in which the
metal atoms are bridged by H2B(im)2 and B(im)4 ligands.160 Unlike poly(pyrazolyl) borates, the
isomeric HnB(im)4_n ligands cannot chelate a metal center but have to bridge between metal ions.
A modified in situ preparation of the chelating monoanionic dicarbene161 and tricarbene ligands162
along with the syntheses of the hexacarbene metal complexes reported by Fehlhammer and co-workers
is shown in Scheme 5. Lanthanide complexes with dihydrobis(benzimidazolyl)borate for which a
seven-coordinate polymeric structure was proposed have been described by Khan and co-workers.163
Scheme 4
1.6.1. Poly-(triazolyl)- (HnB(tz)4-n), –(tetrazolyl)-borates (HnB(tet)4-n)
Although a cobalt complex of hydrotris(1,2,4-triazolyl)borate was reported by Trofimenko in 1967,164
the chemistry of triazolylborate ligands has remained undeveloped for many decades. A convenient
preparation of potassium salt of (H2B(tz)2) was reported by Janiak.165
Scheme 5
27
Scheme 6
Two features of HnB(tz)4-n (Scheme 6) make them attractive candidates for further examination: a) they
should be electron-withdrawing relative to their pyrazolyl-based counterparts; b) the exo ring-nitrogen
atoms of the triazolyl-based ligands can bridge between metal centers, thereby creating coordination
polymers with interesting solid-state structures and optical properties, as shown by Janiak.165 An
unprecedented coordination mode was found in a silver compound where HB(tz)3 bis-chelates the
metal center with two endodentate nitrogen atoms and also bridges to two other silver atoms through
two of the three exodentate nitrogen atoms (Scheme 7a).166 In a copper(II) complex HB(tz)3 utilizes all
six nitrogen atoms in metal coordination, thereby bridging four copper centers and yielding a threedimensional coordination polymer (Scheme 7b).167 The X-ray crystal structures of the iron and cobalt
complexes of HB(tz)3 show the formation of a two-dimensional liquid water phase in the crystal lattice.
Transition metal complexes of H2B(tz)2 are one-dimensional coordination polymers separated by onedimensional arrays of water molecules in the form of edge-sharing six-membered rings. A
dioxomolybdenum compound containing the methyl substituted HB(Me2tz)3 was reported by Xiao.168
The synthesis and structure of the first tetrazolylborate H2B(tet)2 was reported by Janiak which also
employed H2B(tet)2 in the construction of infinite two-dimensional metal–ligand frameworks and onedimensional water substructures.169
Scheme 7
28
1.6.2. Poly(benzotriazolyl)Borates (HnB(Btz)4-n)
In 1988 Lalor reported the synthesis and spectroscopic characterization of some new
poly(benzotriazolyl) borate salts (Scheme 8).170 The regiospecifity of the synthesis of HnB(Btz)4-n
differs from that of pyrazole/BH4- reaction in that B—N bond formation takes place in a manner that
maximizes steric crowding at boron (i.e., at the triazole N(1) atoms). In 1989 Shiu describes some new
metal carbonyls of HB(Btz)3.171 The synthesis and spectroscopic characterization of some first-row
transition metal complexes was reported by Cecchi,172 whereas Hill described some new Rh173 and
Ru174 carbonyl and isonitrile complexes. The formation of isonitrile derivatives was proposed to
proceed through an associative mechanism involving an intermediate complex containing a 1unidentate H2B(Btz)2.175 Two different coordination modes for this family of ligands have been
recently structurally authenticated in a series of copper(I) complexes.176
Scheme 8
1.7.
Poly(pyrazolyl)alkanes
Poly(pyrazolyl)alkanes constitute a family of stable and flexible polydentate ligands isoelectronic and
isosteric with poly(pyrazolyl)borate. These donors can be prepared readily and various substituents
may replace each hydrogen atom, so that electronic and steric effects can be varied nearly at will.
These molecules contain azole rings which are generally very stable towards chemical attack, for
example against both oxidizing and reducing agents. In contrast to poly (pyrazolyl)borates, the
synthesis
and
reactivity
of
their
neutral
and
isosteric
carbon-centered
analogs,
the
poly(pyrazolyl)methanes, is considerably less developed, perhaps due to the relatively small number of
such ligands currently available. However, recent developments in bis(pyrazolyl) methane chemistry,
including the synthesis of potential platinum anticancer agents,177 and the preparation of asymmetric
allylic alkylation,178 olefin hydrogenation, and alkyne hydroamination catalysts have been reported.179
29
1.7.1. Bis(pyrazolyl)alkanes
1.10.5.1.1 Coordination modes of bis(pyrazolyl)alkanes
Bis(pyrazolyl)alkanes, e.g., (RR’C(pz)2) in Scheme 9, are bidentate ligands which have been shown to
afford several types of stable metal complexes. In the growing number of metal derivatives of this
family of ligands some were also characterized through X-ray crystal structures (Sn,180 Nb,181 Pd182,
Mo183). These showed that RC(pz)2 are mainly chelating and fit into several coordination arrangements.
Scheme 9
While 2,2’-bipyridine or phenanthroline adducts are likely to contain an approximately planar, fivemembered –M-N-C-C-N moiety, upon coordination of a RR’ 2C(pz)2 a six-membered cycle is formed
for which a boat conformation is predicted. Nevertheless, both the internal and external angles of the
formally related M-(N-N)2-E moieties (where E is not carbon), are known to be able to undergo wide
variations. Indeed, X-ray studies carried out on several -pyrazolato-N,N’- derivatives showed that the
six-membered ring is not always in the boat conformation. This may undergo a severe folding as in
bis(3,5-dimethylpyrazolyl)borato-N,N’](3-cycloheptatrienyl) (dicarbonyl)molybdenum,184 or may
even
approximate
a
chair,
or
at
least,
a
distorted
chair
as
in
dimeric
bis(cyclopentadienyltitanium)(pyrazolato-N,N’) (Scheme 10a).
The reaction of Me2C(pz)2 with Pt(II) derivatives was investigated. Cleavage of a C(sp3)—N bond in
Me2C(pz)2 is promoted by Pt(II).185 In the compound [(Me2C(pz)2)PdCl2] a Pd…H—C agostic
interaction was found.186
30
Thermolysis of [PhHC(Me2pz)2Mo(CO)4] in DME gives [PhHC(Me2pz)2Mo(CO)3]. Comparison of the
structural details of these two compounds and the reactivity of the latter compound show that it is the
first example containing an intramolecularly coordinated 2-arene ligand (Scheme 10b).187
The reaction between Pd(II) acetate and (H2C(arylpz)2) in refluxing acetic acid affords metallacycles
with two different five- and six-membered palladacycles, one containing an aromatic carbon–metal
bond and the other a pyrazole carbon–metal bond (Scheme 10c).188
Some neutral and cationic palladium(II) (RR’C(pz)2) complexes have been reported by Tsuji and coworkers.189 The cation [(Me2C(pz)2)Pd(CH2=CH2)]+ undergoes ethylene insertion at -10 °C and
oligomerizes ethylene (1 atm) to predominantly linear internal C8 to C24 olefins (ca. 0.1 branches per 2
carbons) at 23 °C. The bidentate ligands (RR’C(pz)2) react with R’’2BX compounds, where X is a
leaving group, to form boronium cations [(RR’C(pz)2)BR’’2]+ isosteric with pyrazaboles and isolable
as PF6- salts.
Gem-(R2C(pz)2) can be lithiated at the inter ring carbon atom to give carbanions which react with a
variety of electrophyles.190 Lithiation can also be directed to the 5-position of the ring.
C-organostannyl and organosilyl derivatives of (Me2C(pz)2) and (H2C(pz)2) have been reported and
characterized spectroscopically.191 Lithiation and subsequent substitution by R3M takes place at the
5,5’-positions
for
both
bis-heterocycles.
Synthesis
and
physicochemical
studies
of
1,2-
bis(azolyl)ethanes are widely reported by Claramunt and co-workers192 whereas the coordination
properties have been investigated193.
Bis(pyrazolyl)propanes were proposed by Ward.194 The 3-(2-pyridyl)-substituted ligand acts as
tetradentate chelate to a single metal ion, forming a variety of mononuclear complexes. The 1H and 13C
NMR of selected (RR’C(pz)2) have been reported by Elguero et al.195 whereas X-ray crystal structures
for the free ligands are reported by Bonati.196
Scheme 10
31
1.7.2. Synthesis of symmetrical bis(pyrazolyl)alkanes
N,N-polyazolylmethanes can be prepared by reaction of azoles with methylene chloride in an autoclave
at 150 °C (Scheme 11). At 200 °C this reaction leads to 4,4’-dipyrazolylmethane, which upon reaction
with boranes gives a pyrazaboles polymer. Some derivatives have been prepared from the reaction of
potassium salts of the azole and methylene iodide. The ligand tetrakis-(1-pyrazolyl)methane was
prepared analogously. In selected cases a basic medium was employed.197
Scheme 11
Methylene chloride is often used in phase transfer catalysis as an inert solvent, and in some cases as a
double alkylating agent. Julia´ et al. demonstrate that phase transfer catalysis is an excellent method to
obtain N,N-diazolylmethanes both by solid–liquid or liquid–liquid procedure.198 Some general
procedures are as follows: (a) a mixture of the azole (29moles), 10ml of 40% aqueous sodium
hydroxide, tetrabutylammonium bromide (1.4mmoles) and 1.2-dibromoethane in 25ml toluene is
heated (external temperature, 60–80 °C) for 24–72 h. After cooling, the aqueous phase is extracted with
3 x 40 ml of dichloromethane and the extract combined with the organic phase and the crude product
obtained is purified by distillation, crystallization, column chromatography on silica gel with
dichloromethane or sublimation. (b) A suspension of azole, anhydrous potassium carbonate
(29mmoles), powdered potassium hydroxide (29mmoles), tetrabutylammonium bromide (1.4mmoles)
and 1,2-dibromoethane (14.5mmoles) in 50ml of toluene or xylene, is heated (external temperature 120
°C) for 48 hours. The hot reaction mixture is filtered and the residue washed twice with 30ml of warm
toluene or xylene. The solution is dried over anhydrous sodium sulfate and then treated as in (a).
The reaction of azoles and benzazoles with dihalomethane and dihaloethanes for the synthesis of
bis(azolyl)methanes and ethanes was also performed in the absence of solvent by solid–liquid phase
transfer catalysis. No solvent was used during the reaction and, when possible, during the work-up.
Comparison with classical P.T.C. methods indicates the usefulness of Phase Transfer Catalysis without
solvent in the synthesis of bis(azolyl)methanes. The advantages are higher yields and milder conditions
by this method. Moreover, P.T.C. in the absence of solvent is a general procedure for the preparation of
32
bis(azolyl)methanes while classical solid–liquid or liquid–liquid P.T.C. methods are used depending on
the azole and this fact could be not rationalized. Finally, the absence of solvent permits the use of
dibromomethane with the less reactive azoles because the alkylation agent is used in an equimolar
amount and not in a large excess (as a solvent). Nevertheless, the regioselectivity obtained by this
method is similar to that described by classical methods.199
When pyrazole rings are bridged by larger alkyl group (isopropylidene) the ligands were better repared
by acid-catalyzed reaction of pyrazole or C-substituted pyrazole with acetals or ketals (Scheme 12).200
Scheme 12
This method, conducted under equilibrating conditions when an unsymmetrically substituted pyrazole
was employed, gives rise to the isomer in which steric interaction between the pyrazole is minimized.
The same procedure was applied to the synthesis of chiral bis(pyrazolyl)methane such as (22). The
metal-catalyzed reaction of 1,10-carbonyldipyrazoles with aldehydes or ketones to give 1,1’alkylidenedipyrazoles and carbon dioxide, the latter being derived from the amide carbonyl group, as
shown by labeling experiments, is sensitive to electronic and steric substituent effects.
(22)
Under comparable reaction conditions, 1,10-carbonyldiimidazole, N-acetylpyrazole, and 1-pyrazoleN,N-diethylcarbonammide do not react with acetone while pyrazole-1-carbo(N-phenylhydrazide)
yields an anilino isocyanate dimer. These results are interpreted in terms of a mechanism that involves
coordination of the metal ion at the 2,2’-nitrogen atoms of the pyrazole rings and heterolytic cleavage
of an amide bond, followed by formation of a carbamate intermediate, decarboxylation and metal ion
exchange.201
33
The multistep syntheses of the novel polyfunctional ligands H2C(3-Ph2Ppz)2 and (Me3SiCH(3Ph2Ppz)2) have been reported by Otero (Scheme 13).202 The coordinating ability of these ligands
towards a variety of early and late metal ions was studied.
Scheme 13
Since an asymmetric pyrazole such as 3(5)-Mepz can exist in two tautomeric structures in solution the
reaction of asymmetric pyrazole with alkylation agents under P.T.C. conditions yields the three isomers
I, II, and III shown in Scheme 14. Generally, the relative amounts of isomeric RR’C(pz)2 (I:II:III)
correspond to (a + b)2. Reaction of 3-(2-pyridyl)pyrazole with CH2Br2 affords only two isomers I and
II,203 whereas 3-(tertbutyl)pyrazole under analogous conditions gives only isomer I.204
Scheme 14
34
The ligand (1,2-(CH2)2(3-Fopz)2) was prepared by reaction of 3-formylpyrazole with 1,2-ditosylateethane and KOt-Bu at -40 °C in thf. It converts, in the presence of copper(II), to the new ligand (1,2(CH2)2(3-Acetalpz)2) which forms polymeric copper(II) complexes with the oxygen atoms from the
acetal fragments semicoordinated to the metal ion, adjusting the coordination sphere to a very distorted
octahedron (Scheme 15). This particular coordination is considered to be the driving force for the
transformation of the aldehyde groups of the initial fragments into the acetal fragments.205
The modification of (H2C(Me3pz)2) by substitution of organotin(IV) groups on the central carbon atom
was carried out by reaction of [HLiC(Me3pz)2] with a triaryltin(IV) chloride. This new ligand shows an
unprecedented 3[N,C,N] coordination mode.206
Scheme 15
Unsymmetrical bis(pyrazolyl)methanes can be obtained according to a general procedure published by
Elguero in 1986.207
1.7.3. Tris(pyrazolyl)Alkanes
Metal complexes of the tris(pyrazolyl)borate ligand system are one of the most widely investigated
classes of coordination compounds. On the other hand the tris(pyrazolyl)alkane ligands RC(pz) 3
(Scheme 16) have received much less attention. RC(pz)3 are suitable for exploring the tendency of
metal ions such as Rh(I) and Ir(I),208 which characteristically form square–planar complexes, to extend
their coordination environment to square–pyramidal or octahedral via axial interactions. The behavior
of the tris(pyrazolyl)methane complex should mirror the behavior of the corresponding
tris(pyrazolyl)borate, the major difference being in the charge between the methane and the borate
counterpart. However, large differences appear in some cases: for example the RC(pz)3 ligands react
with Group 6 metal hexacarbonyls to afford insoluble and involatile species, whereas the neutral
species [(Tp)M(CO)3] are very soluble and sublime easily. The tripodal ligand HC(pz)3 produces a
relatively strong ligand field, consistent with the rather short metal–nitrogen bond lengths in the
35
complexes. The pyrazole group acts as moderately strong  donor and a weak out-of-plane  donor,
with the  interaction in the plane of the amine ligand probably being close to zero.209
Scheme 16
The most common coordination modes include tridentate (a), and bidentate with the third donor group
above the metal center, but uncoordinated (b) or directed away from the metal center (c), as illustrated
in Scheme 16. For example, interaction of (RC(pz)3) with tetrachloropalladate and removal of chloroligands yielded [Pd(L2)]++[X-]2 in which the ligand RC(pz)3 acts as a bidentate ligand to give a square–
planar PdN4 geometry.210 Metalation (d) of (HC(pz)3) can occur with Me2Pt(II) and Ir(III)
complexes.211 Trofimenko showed that as with the tris(pyrazolyl) borate analogs these ligands bind
both early and late transition metals. Canty and co-workers have developed the chemistry of the heavier
metals in Group 10 and 11, showing that (RC(pz)3) is able to stabilize high-oxidation-state
organopalladium(IV) complexes.212,213 Enemark has published several molybdenum complexes
prepared from (HC(Me2pz)3)214 whereas the Ru chemistry was investigated by Meyer215 and
Macchioni.216 Tris(pyrazolyl)methane Ru aquo complexes undergo two pH-dependent, chemically
reversible one-electron oxidation corresponding to the associated Ru(IV)/Ru(III) and Ru(III)/Ru(II)
couples.
Reger used RC(pz)3 ligands to prepare cationic complexes of Na, Fe, Cd, Pb, Ag, Cu and Tl
isoelectronic with known neutral tris(pyrazolyl)borate complexes.217-222 Sn(IV), Ag(I), and Cu(II) were
also reported.223-225 In the silver(I) compounds the ligand acts in a bridging mode.
Four- and five-coordinated precious metal complexes with tris(pyrazolyl)methane have been described,
many
of
which
are
stereochemically
non-rigid.
In
particular,
the
X-ray structure
of
36
[Au(Me2)(HC(pz)3)]NO3 shows a cis-planar coordination, with one pyrazolyl group involved in a weak
axial Au…N interaction.226
Rhodium and iridium complexes of RC(pz)3 show interesting structural and dynamic properties that
shed new light on the chemistry of other pyrazole ligands, a field already vast and rapidly increasing in
importance. Metallotropy was shown to be easier for rhodium that for iridium.
The applications of these ligands have been limited to the work by Nakazawa et al. who found
tris(pyrazolyl)methane titanium complexes to be high-activity catalysts for the polymerization of
olefins, and the use of tris(pyrazolyl)methane zinc complexes to model zinc-containing enzymes, such
as dihydrorootase and carbonic anhydrase.227
1.7.4. Synthesis of tris(pyrazolyl)methanes
Tris(pyrazolyl)methanes were first prepared by Huckel by the reaction of sodium pyrazolate with
chloroform in benzene in 34% yield. Two related methods using THF as solvent were reported by
Trofimenko in 1970.182 The main reason for the lack of chemistry with tris(pyrazolyl)methane ligands
is that the ligands were hard to prepare and a careful column chromatography step was need to purify
them. Phase transfer methods have also been used to synthesize tris(pyrazolyl)methanes, but again, the
yields were still quite low.
Elguero and co-workers reported a solid–liquid phase transfer procedure which involved heating a
mixture of the appropriate pyrazole, chloroform, potassium carbonate and tetrabutylammonium
hydrogen sulfate at reflux overnight.228 The earlier procedure used either liquid–liquid
(dichloromethane with 50% aqueous NaOH as the base) or solid–liquid (dichloromethane with
KOH/K2CO3 as the base) phase transfer conditions. This method was deemed unsuitable for the
synthesis of tris(azolyl)methanes due to the generation of dichlorocarbene and its likely reaction to
produce ring expansion products. Elguero proposed that the tris(azolyl)methane were obtained via
nucleophilic reaction of the azolate anion with chloroform.
Very recently, Reger modified the method of Elguero by heating a mixture of the pyrazole, water,
chloroform, tetrabutylammonium bromide and sodium carbonate at reflux for three days.229
A modification of Elguero’s procedure involved stirring a mixture of 3,5-dimethylpyrazole,
chloroform, potassium carbonate, and tetrabutyl ammonium bromide at room temperature for a week.
During this time the initially colorless reaction mixture became increasingly brown. The separation of
the ligands from the respective reaction mixtures was extremely tedious and difficult (chromatography
or fractional sublimation when the compounds are volatile).
37
Scheme 17
An approach to tris(pyrazolyl)methane containing unsymmetrically substituted pyrazoles was proposed
by Reger (Scheme 17). The conditions of the nucleophilic displacement reaction give rise to a mixture
of regioisomers, that when treated under equilibrating conditions (refluxing toluene, catalytic acid)
result in the conversion to a single regioisomer in which steric interactions are minimized.230
1.8.
Tris(pyrazolyl)MethaneSulfonato
The methyne proton of tris(pyrazolyl)methane is sufficiently acidic to be removed by nBuLi, and the
resulting reactive intermediate readily reacts with electrophiles. Kläui prepared two new anionic
tripodal nitrogen water-soluble ligands (the lithium salts of tris(pyrazolyl)- and tris(3-tertbutylpyrazol)methanesulfonic, Tpms and TmpstBu respectively) by addition of lithiated tris(pyrazolyl) methane to a
sulfur trioxide–trimethylamine complex (Scheme 18).138
A metathesis reaction of this compound with potassium carbonate gave the corresponding potassium
salt. Instead of the boron hydride unit of Tp, Tpms has a methanesulfonate unit, which imparts very
good stability toward hydrolysis and an increased solubility in polar solvents. In contrast to
tris(pyrazolyl)methane Tpms is almost exclusively soluble in water and only moderately soluble in
methanol. The ligand Tpms is stable over a wide range of pH values in aqueous solution. Preliminary
experiments demonstrate that the ligand TmpstBu forms tetrahedral complexes with transition metals
38
that are C3v-symmetric. The Tpms ligand yields a Rh complex [(Tpms)Rh(CO)(PMe3)] which is the
only known catalyst with a tripodal ligand which is active in the catalytic carbonylation of benzene. 231
The Tpms coordinates RhI in a 2 or 3 mode.232
Heterometal cubane-type MFe3S4 clusters, trigonally symmetrized with a Tpms capping ligand, have
recently been reported.233
Scheme 18
2.
Copper and silver derivatives of scorpionates and related ligands
Copper is the center of active sites of many metalloenzymes and metalloproteins, such as hemocyanin
and nitrite reductase. In such metalloenzymes and metalloproteins, each copper atom is coordinated by
the three nitrogen atoms of three imidazoles or histidine groups of proteins. In 1973 the use of the Tp
anion has permitted isolation of the first copper carbonyl complex TpCu(CO).120. Recently, interest in
copper poly(pyrazolyl)borate complexes has been aroused by their resemblance to the active sites in
some copper-containing metalloproteins, TpiPr2 and TpPh2 being useful in the revealing the mode of
dioxygen binding at the copper site of hemocyanin,234,235 while TptBu and TpPh2 have assisted the
development of models for nitric oxide adducts of mononuclear copper in nitrite reductase.119,236,237
[Cu(Tp*)(C2H4)] has also been reported as a catalyst for carbene and nitrene transfer to form
cyclopropanes, cyclopropenes, and aziridines.238 Very recently a series of [Cu(Tpx)] derivatives,
generated in situ, has been reported to catalyze the cyclopropanation of terminal olefins as well as the
industrially important 2,5-dimethyl-2,4-hexadiene.239,240
39
Dias and coworkers in 1996 reported some group 11 metal complexes of fluorinated
tris(pyrazolyl)borates and very recently has described the synthesis of [Ag(Tp (CF3)2)2CN2] which
features a diazoalkane moiety with Ag–O (rather than Ag–N) interactions.241,242 The stability of this
compound suggests that the metal–oxygen bonded species may also play an important role in metalmediated activation of diazoketones.
2.1. Copper poly(pyrazol-1-yl)borates
2.1.1. Bis(pyrazol-1-yl)borates (Bpx) derivatives
Dihydrobis(pyrazolyl)borate and other scorpionate copper(I) (triaryl)phosphino complexes
[Cu(Bpx)(PR′3)2] were firstly reported by Bruce and coworkers,243,244 and further spectroscopically
investigated by Gioia Lobbia in 1995.245 These compounds have been only recently structurally
characterized by Santini.246 Monophosphine [Cu(Bpx)(PR′3)] adducts may be obtained with sterically
hindered donors such as P(o-tolyl)3, the copper centre in these cases achieving three-coordination by
way of bidentate chelation of the ligand (κ2-hapticity), whereas less sterically hindered phosphines such
as PMePh2 and PPh3 allow the attainment of 1:2 [Cu(Bpx)(PR′3)2] adducts (Scheme 19). Dias has
recently reported that fluorinated Bpx ligands yield compounds of similar stoichiometry but with the
scorpionate acting as N,H-donor.247
Scheme 19.
It has been previously reported that [M(Bpx)(L)2] may be subject to boat inversion.248 In the 31P NMR
spectrum of our [Cu(Bpx)(PR′3)2] complexes only one sharp peak is observed, indicating that, unless
there is fortuitous synchronicity, the boat inversion is operating at room temperature.
40
2.1.2. Tris(pyrazol-1-yl)borates (Tpx) derivatives
The first systematic investigation of triaryl- and tricyclohexyl-phosphine copper(I) complexes
containing anionic tris(pyrazol-1-yl)borates,249 prepared from the metathetic and displacement reaction
(1) in chlorinated solvents, was reported seven years ago.
[Cu(NO3)(PR′3)2]+MTpx→[Cu(Tpx)(PR′3)]+PR′3+MNO3 (M=Na or K,R=cy or aryl)
(1)
Four-coordinate Cu(I) species, in a tetrahedral configuration strongly distorted because of the bulky
PR′3 and Tpx ligands, were always obtained (Fig. 2). We have found that these compounds can be
prepared more efficiently by using a Cu(I) starting material such as [CuBr(Me 2S)] or
[Cu(C6H6)0.5(O3SCF3)]2.246 The [Cu(Tpx)(PR′3)] complexes are generally soluble in chlorinated
solvents, acetone and DMSO in which they are non-electrolytes. They are air-stable but decompose in
solution in accordance with non-ionic equilibria such as (2), followed by disproportionation of the well
known polynuclear complexes104,106,250 to copper metal and copper(II) species (3). Attempted reactions
of [Cu(Tpx)(PR′3)] with imidazole, pyrazole, bipyridyl or phenanthroline were unsuccessful, the
starting materials always being recovered.
n[Cu(Tpx)(PR′3)]→[Cu(Tpx)]n+nPR′3
(2)
2[Cu(Tpx)]n→n[Cu(Tpx)2]+nCu
(3)
Fig. 2.
41
Kitajima reported that displacement of the carbonyl group in a mononuclear copper complex
[Cu(Tp*)(CO)] with PPh3 can afford [Cu(Tp*)(PPh3)] quantitatively. The reaction of [Cu(Tp*)(PPh3)]
with an excess amount of PhIO results in the formation of a μ-oxo dinuclear copper(II) complex
[Cu(Tp)]2O which immediately converts to a bis(μ-hydroxo) dinuclear species [Cu(Tp)]2(μ-OH)2.110
Volatility studies, electrospray mass spectra and IR in vapour phase have been carried out for selected
[Cu(Tpx)(PR′3)] complexes.251 The volatility has been related to structural features and molecular
parameters of the copper(I) complexes. These compounds are much more volatile than copper(I)
pyrazolonates and seem to be promising precursors for thin film deposition as the heterocyclic rings in
the ligand are not involved in the conjugation and do not contain additional donor centres. XRD data of
films obtained from metal organic chemical vapor deposition MOCVD on [Cu(Tpx)(PR′3)] and
[Cu(Bpx)(PR′3)n] (n=1 or 2) complexes have been also reported.251
By using the water-soluble P-donor ligand 4-(diphenylphosphane)benzoic acid, some water-soluble
copper(I) complexes [Cu(Tpx){PPh2(4-C6H4COOH)}] have recently been obtained which have been
investigated by chemiluminescence techniques in order to evaluate their superoxide scavenging
activity.252
A series of Cu(Tpx)2 derivatives (Tpx=TpMe3, Tp4Me, Tp*Cl, Tp3Me) were synthesised and
spectroscopically characterized in 1999.253 These complexes, with the metal in a strongly distorted
octahedral environment (Fig. 3) (X-ray studies), have been also characterized by fast atom
bombardment spectrometry and magnetic susceptibility measurements.
Fig. 3.
2.1.2. Tetrakis(pyrazol-1-yl)borate (pzoTpx) derivatives
Tetrakis(pyrazolyl)borate copper(I) bis(triaryl)phosphino species [Cu(pzoTpx)(PR′3)2] (Fig. 4(a)) were
reported in 1995 and characterized by way of IR, 1H,
13
C and
31
P NMR measurements.245 These
compounds are more stable in solution with respect to the analogous Tpx and Bpx derivatives. They are
42
fluxional in solution, all pyrazolyl groups being equivalent down to −60 °C. Selected
[Cu(pzoTpx)(PR′3)2] derivatives have been characterized by IR in the gas phase across a wide
temperature range, confirming the stability of these species and suggesting the molecular structure in
vapour to be similar to that previously determined by single crystal X-ray studies. The dependence of
the volatility on the number of the pyrazolyl moieties has been discussed, the pz oTpx derivatives being
more volatile with respect to Bpx and Tpx derivatives containing the same phosphine.
Fig. 4.
More recently monophosphine [Cu(pzoTpx)(PR′3)] (Fig. 4(b)–(c)) species have been reported as well
with two different structurally authenticated arrays: (i) [Cu(pzoTpMe)(Pcy3)], with a three coordinate
PCu(N)2 coordination environment and the donor with κ2-hapticity and (ii) [Cu(pzTp)(P(p-tolyl)3)],
with a four coordinate PCu(N)3 metal core and the scorpionate with κ3-hapticity.246
The strongly distorted octahedral Cu(pzoTpMe)2 and Cu(pzoTp4Me)2 have been also described. In these
compounds the ligands act as tripodal N3-donors; complexation of the fourth pyrazole ring and
formation of polynuclear or oligonuclear species has never been observed.253
2.2. Copper poly(triazol-1-yl)borates
Although a cobalt complex of hydrotris(1,2,4-triazolyl)borate was reported by Trofimenko in 1967,254
the chemistry of poly(triazolyl)borate (HnB(tz)4 − n) species (Fig. 5) has remained undeveloped.
Fig. 5.
43
Two features make them attractive candidates for further examination: they should be electronwithdrawing relative to their pyrazole-based counterparts, and the properties of metal complexes
should differ accordingly; the exo ring nitrogen atoms of triazole-based ligands may bridge between
metal centers, thereby creating coordination polymers with interesting solid state structural and optical
properties as recently shown by Janiak.166 We have recently reported several copper(I) coordination
polymers as well as mononuclear copper complexes derived from poly(1,2,4-triazolyl)borate ligands
and triorganophosphines.255 The structurally authenticated arrays fall into four different types (Fig. 6):
(a) discrete mononuclear bis(triazolyl)boratebis(triorganophosphine) copper(I) species; (b) discrete
mononuclear tris(triazolyl)borate(triorganophosphine)copper(I) species, with CuN3P coordination
spheres; (c) one dimensional polynuclear species containing bis(triazolyl)borate wherein the triazolyl
groups are coordinated throughout both N2 and N4 within CuN3P coordination spheres; (d) onedimensional polynuclear species containing tris(triazolyl)borate, wherein one of the triazolyl rings is
uncoordinated and the other two bridge through the N to successive copper atoms. Two
[Cu(HnB(tz)4 − n){PPh2(4-C6H4COOH)}] (n=1 or 2) have been also reported.252
Fig. 6.
44
2.3. Copper poly(benzotriazol-1)borates
Fig. 7.
A series of copper(I)(PR′3)n (n=1 or 2) complexes of {HxB(btz)4 − x} (Fig. 7) (x=1 or 2) has been
synthesised and characterized by X-ray studies, and by IR and NMR spectroscopy.176 1:1:1 and 1:2:1
Cu:PR′3: {HxB(btz)4 − x} species were afforded, depending on the nature of the P-donor, and in some
cases, on the reaction conditions employed. All species are of limited stability in solution and fluxional
at room temperature. The {HxB(btz)4 − x} ligand is able to coordinate in uni-, bi- or tri-dentate fashion,
coordination occurring not only through the three N2 atoms, but also through one N3 atom. Two
structurally authenticated arrays were found: (i) [Cu{H2B(btz)2}(PBn3)2] with a three coordinate
P2CuN coordination sphere and the donor coordinated throughout only one N3 atom (Fig. 8(a)); (ii)
[Cu{HB(btz)3}{P(m-tolyl)3}] with a four coordinate PCuN3 coordination sphere, and the {HB(btz)3}
acting as tripodal donor by way of all N2 atoms (Fig. 8(b)).
Fig. 8.
A copper(II) derivative, [Cu{HB(btz)3}2], has also been reported and characterized by IR and EI MS
spectra.
45
2.4. Copper(I) hydrotris(3-methyl-2-thioxo-1-imidazolyl)borates
1:1:1 [Cu(Tm)(PR′3)] triorganophosphine copper(I) complexes containing the anionic, potential S3donor face-capping ligand hydrotris(3-methyl-2-thioxo-1-imidazolyl)borate Tm− [9] (Fig. 9) were
synthesised from K(Tm), CuCl and the corresponding P-donor. The copper atoms are tetracoordinated,
the Tm− behaving as a tripodal donor (Fig. 10). In the absence of P-donors Cu(I) salts react with K(Tm)
yielding a possibly polynuclear [Cu(Tm)]n species which is unreactive toward NH3, CS2, H2O and CO,
but reacts with pyridine yielding [Cu(Tm)(py)]. [Cu(Tm)]n reacts with H2O2 yielding the poorly soluble
[Cu(mimt)]n (Hmimt=3-methyl-1-imidazoline-2-thione) upon breaking of the B–N bond in the
mercaptoimidazolylborate ligand.256
Fig. 9.
Fig. 10.
46
2.5. Copper(I) heteroscorpionate derivatives
Interest in the coordination chemistry of new heteroscorpionates monoanionic ligands, N-, O- or Sdonor is increasing. Some recent papers report the synthesis of the tris(pyrazol-1-yl)methane sulfonate
ligand (Tpms) which is highly water soluble and stable over a wide pH range ligand.138 Its interaction
with CuCl in the presence of PR′3 has provided a series of new copper(I) coordination compounds of
formula [Cu(Tpms)(PR′3)] (Scheme 20) and also a copper(II) species [Cu(Tpms)2] when R is
cyclohexyl. [Cu(Tpms)(PPh3)] is the first example of structurally characterised complex containing
Tpms coordinated to a metal ion in an unusual κ3-N,N′,O fashion.257
Scheme 20
2.6. Copper poly(azol-1-yl)alkanes
2.6.1. Bis(azolyl)alkane derivatives {(Az)2CH2}
The interaction of a bis(azol-1-yl)alkane (Az)2CH2 (Az=pyrazole or triazole) with [CuX(PR′3)2]
(X=NO3,
BF4,
ClO4,
halide)
can
yield
ionic
[Cu{(Az)2CH2}(PR′3)2]+X−
or
neutral
[CuX{(Az)2CH2}(PR′3)] derivatives upon displacement of X− or PR′3, respectively, from the copper
coordination sphere.258,259 The stoichiometry and structure of the complexes are dependent on the
nature of the substituent on the azolyl group and also on the nature of the counter-ion X. As an example
in the Scheme 21 the reaction of [CuNO3(PR′3)2] with several (pzx)2CH2 is described. Displacement of
the nitrate is observed with the less hindered and less basic ligands of the family such as pz2CH2.
47
Scheme 21
Nevertheless, one PR′3 may be displaced from [CuNO3(PR′3)2] by the more bulky and more basic
(pz*)2CH2. By contrast, no difference in behaviour has been observed with the arsine and stybine
derivatives [CuNO3(AsPh3)3] and [CuNO3(SbPh3)3] which always yield [CuNO3{(pzx)2CH2}(EPh3)]
derivatives. Displacement of all the phosphine ligands to yield [Cu{(pzx)2CH2}2]+X− is possible
although forcing conditions are required, i.e. strong excess of the N2-donor ligand in refluxing benzene.
The compounds [Cu{(Az)2CH2}2]+X− can be more efficiently prepared from [CuNO3(SbPh3)3] taking
advantage of the decreasing strength of the metal-E bond in the sequence P, As and Sb. The reactivity
of the bis(azol-1-yl)alkanes towards [Cu(PR′3)4]ClO4 is summarized (Scheme 22).
48
Scheme 22
2.6.2. Tris(pyrazol-1-yl)methanes derivatives {HC(pzx)3}
The interaction of CuX2 (X=ClO4, NO3, Cl, Br, O2CCH3) with excess of tris(pyrazol-1-yl)methane
HC(pzx)3 yielded [CuX2{(pz)3CH}], [{CuX2}3{(pz)3CH}2] or [{Cu{(pz)3CH}2}]X2 depending on the
substituents on the azolyl moiety and, more particularly, on the nature of the counter-ion.225 All
complexes have been characterized by analytical and spectroscopic measurements (IR, UV, and
conductivity measurements) and also in the case of the strongly distorted octahedral
[{Cu{(pz)3CH}2}]X2 species, by X-ray diffraction studies.
2.7. Silver(I) poly(pyrazol-1-yl)borate
2.7.1. Bis(pyrazol-1-yl)borates derivatives
Silver(I) derivatives containing triorganophosphine and bis(pyrazolyl)borates were synthesised in 2000
by the reaction of AgNO3 with K(Bp) and K(Bp*) in the presence of PR′3 in methanol.260 They have
been characterized both in the solid and solution state through analytical and spectroscopic
measurements. They are air- but not solution-stable. The structures of [Ag(Bp)(PPh3)2],
49
[Ag(Bp*)(Pcy3)] and [Ag(Bp*)(PEtPh2)] have been determined by X-ray crystallographic studies. In
these compounds Bp and Bp* are bidentate, with their silver(I) centres adopting tetrahedral (a) or
trigonal geometries (b) (Fig. 11). The 31P NMR data show that the bis(triorganophosphino)derivatives
are more stable than the mono-organophosphino species and that the stability decreases with increasing
cone angle of the P-donor.
Fig. 11.
We have also investigated the reactivity of K(Bp) and K(Bp*) toward AgNO3 in the presence of
bidentate diphosphines such as dppm, dppe, dppp, dppb and dppf. The 1H and
31
P NMR spectra have
been interpreted with equilibria that involve mono- and di-nuclear species, or the presence of 1:1 and
1:2 silver:diphosphine adducts. The structure of [Ag(Bp)(dppf)] as determined by single crystal X-ray
studies indicates the Bp to be bidentate, with the silver centre in a distorted tetrahedral geometry (Fig.
12).261 No derivative containing Bpx and CNR ligands simultaneously coordinated to silver(I) has been
to date reported.
Fig. 12.
2.7.2. Tris(pyrazol-1-yl)borates derivatives
The silver derivatives [Ag(Tp*)]2, [Ag(Tp4Br)]2, and [Ag(Tp)2],151 have been synthesised and
characterized by IR and NMR spectroscopy. The complexes [Ag(Tp*)]2 and [Ag(Tp4Br)]2 are fluxional
with a pyrazolyl ring exchange process occurring rapidly at 293 K, but not at 193 K, whereas
[(Ag(Tp)2] and the crystalline form of [Ag(Tp*)]2 are not fluxional even at room temperature. The
50
structure of [Ag(Tp*)]2 as described by McCleverty and coworkers and substantiated by our own work,
despite substitution, is not that of its copper(I) homologue, with no bridging pyrazolate units, but
rather, that of the unsubstituted parent [Cu(Tp)]2 with N2M(μ-N) metal atom environments (Fig. 13),
presumably a consequence of greater flexibility contingent upon the incorporation of the larger (silver)
metal atom.262
Fig. 13.
Trialkyl- and triaryl-phosphine silver(I) derivatives containing anionic tris(1H-pyrazolyl)borates
[Ag(Tpx)(PR′3)] were prepared from AgX (X=OTf or NO3), PR′3 (R′=Ph, Bn, cy, o-, m-, p-tolyl, Mes)
and MTpx, Tpx=Tp, Tp4Br, Tp*, TpPh2; M=Na or K).263-265 These air-stable, light sensitive complexes,
are non-electrolytes in dichloromethane and acetone, and have been characterized through analytical
and spectral measurements. The X-ray diffraction studies show that the silver atom adopts a distorted
tetrahedral geometry. [Ag(Tpx)(PR′3)] (Fig. 14(a)) generally decompose in acetone solution, even with
strict exclusion of oxygen and light. Comparison of the Ag–N bond lengths suggests the bonding of
Tpx to the Ag(PR′3)+ fragment to be similar despite the steric and electronic differences of the
supporting ligand PR′3. The magnitude of the silver–phosphorus coupling constant and the 31P chemical
shift indicate that the structure and the stability of complexes in solution is strongly dependent on the
Tolman cone angle and pKa of PR′3. We have also found that, in [Ag(Tpx)(PR′3)], it is possible to
displace the PR′3 donor from the Ag(I) center with a more basic triorganophosphine, but not with a
neutral N-donor mono or bidentate, such as imidazoles, pyrazoles or phenanthroline.
Fig. 14.
51
Despite the large number of papers describing Group 11 poly(pyrazol-1-yl)borate derivatives, relatively
little attention has been devoted to systems which also contain small unsaturated molecules such as CO
and CNR.68,266-270 Complexes of the formula [Ag(Tpx)CNR] (Tpx=Tp* or TpPh2; R=cy or tBu) (Fig.
14(b)) have been generally obtained independently under the reaction conditions employed when the
reaction between Tp* and silver salts was carried out in the presence of isonitrile ligands [309], no
derivatives being obtained when the unsubstituted Tp was used. Those [Ag(Tpx)CNR] structurally
characterized are all unsolvated mononuclear arrays with tripodal Tpx and unidentate CNR making up
the four coordinate environment of the silver atom.
2.7.3. Tetrakis(pyrazol-1)borate derivatives
A systematic investigation of the interaction between silver(I) and the anionic tetrakis(pyrazol-1yl)borates pzTp and pzoTpMe was reported in 1998. These complexes are generally more stable in
solution than the analogous derivatives obtained with Bp and Tp ligands. At room temperature, in
CDCl3 solution the six-membered AgN4B rings formed by pzTp and pzoTpMe are fluxional, probably
undergoing a rapid dissociation-reassociation mechanism (boat–boat flip), whereas at low temperature
a process which equilibrates only three pyrazolyl rings, with the fourth remaining uncoordinated, is
likely. Room-temperature single crystal structural characterizations showed that the scorpionate ligand
may be bidentate or tridentate, with a three- or four-coordinate array about the silver. The variation in
the silver(I) coordination number and environment in various combinations of various degrees of steric
interaction among the above entities has been explored and structures similar to those described for
Cu(I) have been found. The interaction of pzTp and pzoTpMe with silver(I) in the presence of chelating
bidentate diphosphines was also investigated. The silver(I) tetrakis(pyrazol-1-yl)borates [Ag(pzTp)]n
and [Ag(pzoTpMe)]n have been also reported and their spectroscopic features and reactivity toward
imidazole described. The silver isonitrile derivatives [Ag(pzTp)CNR] and [Ag(pzoTpMe)(CNR)x] (x=1
or 2) have been successfully synthesised. They exhibit a fluxional behaviour in solution with a
pyrazolyl ring exchange process occurring rapidly even at 218 K. Reaction of [Ag(pz oTpMe)(CNcy)2]
with Hmimt and ImH yield [Ag(mimt)]n and [Ag(pzoTpMe)(CNcy)(ImH)], respectively, whereas
reaction of [Ag(pzTp)(CNtBu)] with ImH yields [Ag(pzTp)(ImH)].271
52
2.8. Silver(I) hydrotris(3-methyl-2-thioxo-1-imidazolyl)borates
1:1:1 [Ag(Tm)(PR′3)] triorganophosphine silver(I) complexes were synthesised in methanol from
K(Tm), AgNO3, and the corresponding PR′3 donor.150 In [Ag(Tm)(Pcy3)] (Fig. 15) the silver atom are
tricoordinated, with the donor Tm behaving as an S2-donor. A short Ag B distance suggests the
existence of a two-electron B–H Ag agostic interaction. The syntheses of the 1:1:2
[Ag(Tm)(PEtPh2)2] and the 2:2:1 [Ag2(Tm)2P(m-tolyl)3] were also reported. The complex [Ag(Tm)]2,
obtained in methanol from the methathesis reaction of AgNO3 with K(Tm), in the chloroform solvate
form [Ag(Tm)]2 · 2CHCl3, has been shown to be dinuclear, the core of the dimer (Fig. 16) being a fourmembered Ag(μ-S)2Ag ring, the two sulfur atoms of the bridging mercaptoimidazolyl rings
coordinating two silver atoms in somewhat unsymmetrically mode. The B–H groups of the Tm ligand
is disposed with the hydrogen atom projecting into the Ag2S2 ring. The silver coordination environment
is completed by two sulfur atoms from the remaining mimt rings.151
Fig. 15.
Fig. 16.
53
2.9. Silver(I) poly(imidazolyl)borates
The anionic dihydrobis(imidazolyl)borates [H2B(im)2]− and tetrakis(imidazolyl)borate [B(im)4]− (Fig.
17) react with AgNO3 in the presence of PR′3 yielding binuclear [Ag(PR′3)2{(im)BX2(im)}]2 (X=H or
im) (Fig. 18(a)) or polymeric compounds [Ag(PR′3){(im)BX2(im)}]n compounds (Fig. 18(b)). Solution
data are consistent with a partial dissociation of complexes, occurring through breaking of both Ag–N
and Ag–P bonds. In particular the
31
P NMR data indicate that the structure and stability are strongly
dependent on the stoichiometry and on the Tolman cone angle of the phosphorus donor ligand.
[Ag{(im)BH2(im)}(Pcy3)]n is a single stranded polymer containing three-coordinate silver atoms
(PAgN2 core), while in [Ag{(im)B(im)2(im)}(Pcy3)2]2 the silver atoms are four-coordinate with
P2AgN2 cores.160
Fig. 17.
Fig. 18.
54
2.10. Silver poly(azolyl)alkanes
2.10.1. Bis(pyrazolyl)alkanes
Bis(pyrazolyl)-methanes and -ethanes react with AgX species (X=NO3, ClO4, O3SCF3, O3SCH3,
O2CCH3, BF4) yielding complexes of different stoichiometry dependent on the nature of X.272,273 The
bis(pyrazolyl)alkane/silver ratio rises from 0.5 in [(Ag(O3SCH3))2{(pz4NO2)2(1,2-C2H4)}] to 2 in the
distorted tetrahedral [Ag{(pz)2CMe2}2]ClO4 (Fig. 19). The (pz)2CH2 ligand reacts with AgNO3
yielding a 1:1 neutral species whereas with Ag(O2CCH3) a polynuclear [Ag(pz)]n species is formed,
presumably following hydrolysis of the acetate and breaking of the bridging C-N bond in the organic
ligand.
Fig. 19.
2.10.2. Tris(pyrazolyl)alkanes
The reaction of AgX (X=ClO4, NO3, O3SCH3) with excess of tris(pyrazolyl)methane ligand (pzx)3CH
(Hpzx=Hpz, Hpz4Me, Hpz*, HpzMe3) yields 1:1, 2:1 or 3:2 complexes. The ligand to metal ratio is
dependent on the number and disposition of the methyls on the azole ring and primarily on the nature
of the counter-ion X. IR, NMR and conductivity measurements have been reported for all complexes.
Ag(NO3):(pz)3CH 1:1 crystallizes with two formula units devoid of crystallographic symmetry as the
asymmetric unit of the complex which is an infinite, unsolvated, two dimensional polymer, lying
parallel to the ac plane. The Ag(2) atom in Fig. 20 has a tris(bidentate) environment due to a pairs of
pyrazolate N from each of the independent (pz)3CH ligands and approximately bidentate nitrate,
whereas Ag(1) is five-coordinated by three pyrazolate from three independent pz3H and one bidentate
nitrate.224
55
Fig. 20.
In Ag(NO3):(pz)3CH 1:2, each ligand behaves as a tripod, the silver atom being in a strongly distorted
octahedral environment (Fig. 21).274
Fig. 21.
2.10.3. Bis(triazol-1-yl)methanes
Only few examples of triazolylalkane complexes have been to date reported, because of the ready
formation of polymeric insoluble species. We have had success in the synthesis of a series of soluble
silver complexes containing the tz2CH2 ligand.275 The structure of AgNO3:tz2CH2 1:1 is based on a
silver atom essentially linearily coordinated from different rings of different ligands. Polymer strands
overlaid with juxtaposed silver atoms have the latter weakly bridged by only one of the nitrate oxygen
56
atoms which interacts significantly, further feeble cross-linking in the third dimension occurring by
way of another nitrogen atom (Fig. 22(a)). The character of the silver(I) nitrite:tz2CH2 (1:1) adduct is
quite different, two formula units comprising the asymmetric unit of the structure. The coordination of
the first silver is quasi linear as in the nitrate counterpart. Perturbation of the coordination occurs
through the approach of a nitrogen of another triazolyl group and a nitrite nitrogen, but the remainder
of the coordination sphere of the latter is made up of a pair of nitrite chelates (Fig. 22(b)). The 4:3
adduct between tz2CH2 and silver(I) triflate is devoid of metal-anion interactions, with concomitant
increase in salt ligand stoichiometry. One AgO3SCF3:(tz2CH2) (3:4). MeCN formula unit comprises the
asymmetric unit of the structure with the (Ag3(tz2CH2)4)3+ cation array polymeric (Fig. 22(c)).
Fig. 22.
57
Chapter 2
New (diphenylphosphane)benzoic acid copper(I)
derivatives of ‘‘scorpionate’’ ligands with superoxide
scavenging activity
Free radicals are involved in a cascade of events that lead to conditions of oxidative stress in biological
systems and to a number of many pathological diseases. This part of scientific research has been
dedicated to studying the role of antioxidants, synthetic and natural, that can mitigate the deleterious
effects induced by these species. A group of synthetic compounds which have recently been exploited
from the antioxidant perspective are (diphenylphosphane)benzoic acid copper(I) derivatives of
“scorpionate” ligands.252 This new class of copper(I) compounds was studied in relation to the possible
antioxidant activity of these complexes as scavengers of superoxide anion. Here, we reported a new
study on synthesis and on antioxidant activity of different copper(I) complexes.
Poly(azolyl)borates or scorpionate ligands276 have been successfully used as supporting ligands for
bioinorganic synthetic studies. In particular, a number of poly(pyrazolyl)borate copper derivatives,
synthesized in order to model various properties of copper-containing natural products, have been
discussed in a review devoted to the structure and function of copper proteins.277 Besides, since the
obtainment of complexes that are soluble and stable under physiological conditions is of great
importance, the use of water soluble phosphane co-ligands bringing highly polar functional groups such
as –SO3Na, –COOH, –NR3+, or –OH groups is an interesting new research field.278,279
In the last years, we have initiated an investigation into the coordination chemistry of new scorpionate
monoanionic ligands, N- or S-donors, towards early transition metal centres.263 This paper describes the
synthesis and the spectroscopic and analytical characterization of new bis-, tris- and tetrakis(azolyl)borates containing copper(I) and 4- or 2-(diphenylphosphane)benzoic acid coligands.
Besides, we tested the superoxide scavenging activity of these new copper complexes by using
chemiluminescence technique.280 The capacity of these complexes to act as scavengers of superoxide
58
anion has been compared with the enzyme superoxide dismutase and with the nitroxide radical Tempo,
a compound known to possess SOD-mimic activity.281
1. Experimental
section
1.1. General procedures
All syntheses and handling were carried out under an atmosphere of dry oxygen-free dinitrogen, using
standard Schlenk techniques or a glove box. All solvents were dried, degassed and distilled prior to use.
Xanthine, xanthine oxidase (E.C.1.1.3.22), superoxide dismutase (E.C.1.15.1.1) from bovine
erythrocytes, Tempo and lucigenin were obtained from Sigma-Aldrich Chemical Co.
Elemental analyses (C, H, N, S) were performed in house with a Fisons Instruments 1108 CHNS-O
Elemental Analyser. IR spectra were recorded from 4000 to 100 cm−1 with a Perkin–Elmer System
2000 FT-IR instrument. 1H- and
31
P-NMR spectra were recorded on a VXR-300 Varian spectrometer
(300 MHz for 1H, and 121.4 MHz for
31
P). Electrospray mass spectra were obtained in positive- or
negative-ion mode on a Series 1100 MSD detector HP spectrometer, using a methanol mobile phase.
The compounds were added to the reagent grade methanol to give solutions of approximate
concentration 0.1 mM. These solutions were injected (1 μl) into the spectrometer via a HPLC HP 1090
Series II fitted with an autosampler. The pump delivered the solutions to the mass spectrometer source
at a flow rate of 300 μl min−1, and nitrogen was employed both as a drying and nebulizing gas.
Capillary voltages were typically 4000 and 3500 V for the positive- and negative-ion mode,
respectively. Confirmation of all major species in this ESIMS study was aided by comparison of the
observed and predicted isotope distribution patterns, the latter calculated using the IsoPro computer
program.
Chemiluminescence measurements were performed using lucigenin as chemiluminogenic probe and
superoxide radical was produced by the xanthine/xanthine oxidase system. The chemiluminescence
(CL) was measured in Autolumat LB953 (Berthold Co. Wildbad, Germany) in a reaction mixture
containing 0.9 U/ml xanthine oxidase, 150 μM lucigenin in Tris 50 mM, pH 7.4 buffer and different
concentrations of compounds dissolved in ethanol. The reaction was started by injecting xanthine at a
final concentration of 50 μM. Lucigenin-amplified CL, produced by superoxide anion and generated
from the xanthine/xanthine oxidase system, showed a peak value in
reaction (injection of xanthine); the reaction termined after
10 s after initiation of the
40 s. The peak value indicated the
presence of O2− in the medium. It was due to the light emission (photons) during the reaction that was
59
revealed by chemiluminescence detector as counts per second (cps). Data (reported as mean
values ± standard deviation) refer to at least three individual experiments.
1.2. Synthesis
All reagents were purchased from Aldrich and used without further purification. The potassium
dihydrobis(1H-benzotriazol-1-yl)borate, KH2B(btz)2, potassium hydrotris(1H-benzotriazol-1-yl)borate,
KHB(btz)3, sodium hydrotris(1H-3-methylpyrazol-1-yl)borate, NaTpMe, potassium tetrakis(1H-pyrazol1-yl)borate, KpzTp, potassium tetrakis(1H-3-methylpyrazol-1-yl)borate, KpzTpMe, were prepared in
accordance with
the procedure first
reported by Trofimenko.164
The ligand potassium
dihydrobis(imidazolyl)borate dimethylacetamide, [K{H2B(im)2} (dmac)], was synthesized in
accordance with the literature methods.160
1.3. {Cu[PPh2(4-C6H4COOH)]2H2B(btz)2} (1)
To a CH3OH/CH3CN (1/1) solution (50 ml) of CuCl (0.099 g, 1.0 mmol) and [PPh2(4-C6H4COOH)]
(0.613 g, 2.0 mmol), K[H2B(btz)2] (0.288 g, 1.0 mmol) was added at room temperature. After the
addition, the solution was stirred for 3 h and the solvent subsequently removed with a rotary
evaporator. CHCl3 (50 ml) was added. The suspension was filtered and concentrated under reduced
pressure. A colourless precipitate was formed, which was filtered off and washed with diethyl ether.
Re-crystallization from CH2Cl2-petroleum ether gave complex 1 as a microcrystalline solid in 76%
yield, m.p. 167 °C. 1H NMR (CDCl3, 293 K): δ 7.18–7.75 (m, 36H, CH). 31P{1H} NMR (CDCl3, 293
K): δ −3.6 (sbr).
31
P{1H} NMR (CDCl3, 218 K): δ 34.8 (s), −3.5 (s), −1.4 (sbr). IR (nujol, cm−1):
3169w (CH); 2431m (BH); 1690sbr (C=O); 1597m (C=C + C=N); 532s, 508s, 482m, 434m (Ar3P);
303w. ESIMS (CH3OH): (−) 249 (100) [H2B(btz)2]−, 347 (40) [CuCl{H2B(btz)2}]−. ESIMS (CH3OH):
(+) 619 (40) [{H2B(btz)2}Cu{PPh2(4-C6H4COOH)} + H+]+, 675 (100) [Cu{PPh2(4-C6H4COOH)}2]+,
1475 (25) [Cu4{PPh2(4-C6H4COO)}4 + H+]+. Anal. Calc. for C50H40BCuN6O4P2: C, 64.9, H, 4.4; N,
9.1. Found: C, 64.8; H, 4.5; N, 8.9%.
1.4. {Cu[PPh2(2-C6H4COOH)]2H2B(btz)2} (2)
Compound 2 was prepared similarly to compound 1, by using CuCl (0.099 g, 1.0 mmol), [PPh2(2C6H4COOH] (0.613 g, 2.0 mmol) and K[H2B(btz)2] (0.288 g, 1.0 mmol) in CH3CN/methanol (1:2)
solution. Re-crystallization from CHCl3 gave complex 2 as a micro-crystalline solid in 62% yield, m.p.
60
153 °C. 1H NMR (CDCl3, 293 K): δ 6.91–8.04 (m, 36H, CH). 31P{1H} NMR (CDCl3, 293 K): δ 1.3 (s).
P{1H} NMR (CDCl3, 218 K): δ 1.9 (sbr). IR (nujol, cm−1): 3169w (CH); 2424m (BH); 1677sbr
31
(C=O); 1560m (C=C + C=N); 535m, 525s, 504sbr, 449sh, 431m (Ar3P). ESIMS (CH3OH): (−) 249
(100)
[H2B(btz)2]−,
347
(20)
[CuCl{H2B(btz)2}]−.
ESIMS
(CH3OH):
(+)
619
(30)
[{H2B(btz)2}Cu{PPh2(2-C6H4COOH)} + H+]+, 675 (100) [Cu{PPh2(2-C6H4COOH)}2]+. Anal. Calc. for
C50H40BCuN6O4P2: C, 64.9, H, 4.4; N, 9.1. Found: C, 64.7; H, 4.5; N, 8.8%.
1.5. {Cu[PPh2(4-C6H4COOH)]HB(btz)3} (3)
Compound 3 was prepared similarly to compound 1, by using CuCl (0.099 g, 1.0 mmol), [PPh2(4C6H4COOH] (0.613 g, 2.0 mmol) and K[HB(btz)3] (0.405 g, 1.0 mmol) in CH3CN/methanol (1:2)
solution. Re-crystallization from CHCl3/diethyl ether (1:3) gave complex 3 as a micro-crystalline solid
in 59% yield, m.p. 184 °C. 1H NMR (d6-acetone, 293 K): δ 7.40–8.33 (m, 26H, CH).
31
P{1H} NMR
(d6-acetone, 293 K): δ 5.6 (sbr). 31P{1H} NMR (d6-acetone, 218 K): δ 4.6 (s), −5.1 (s). IR (nujol, cm−1):
3190w, 3141w (CH); 2490m (BH); 1701sbr (C=O); 1558m (C=C + C=N); 540s, 514s, 437m (Ar3P);
303w. ESIMS (CH3OH): (−) 366 (100) [HB(btz)3]−. ESIMS (CH3OH): (+) 711 (100) [CuCl{PPh2(4C6H4COOH)}2 + H+]+. Anal. Calc. for C37H28BCuN9O2P: C, 60.4, H, 3.8; N, 17.1. Found: C, 60.0; H,
4.0; N, 16.9%.
1.6. {Cu[PPh2(4-C6H4COOH)]TpMe} (4)
To a methanol solution (50 ml) of CuCl (0.099 g, 1.0 mmol) and [PPh2(4-C6H4COOH] (0.613 g, 2.0
mmol), NaTpMe (0.278 g, 1.0 mmol) was added at room temperature. After the addition, the solution
was stirred for 6 h. The colourless precipitate obtained was filtered off and washed with diethyl ether.
Re-crystallization from CHCl3/petroleum ether (1:3) gave complex 4 as a micro-crystalline solid in
74% yield, m.p. 161 °C. 1H NMR (CDCl3, 293 K): δ 1.76 (s, 9H, 3-CCH3), 5.85 (d, 3H, 4-CH), 7.35–
7.43 (m, 14H, CH), 7.54 (d, 3H, 5-CH).
P{1H} NMR (CDCl3, 293 K): δ −1.6 (br);
31
31
P{1H} NMR
(CDCl3, 218 K): δ −4.8 (s), 5.0 (br), 32.4 (s). IR (nujol, cm−1): 3061w (CH); 2460m (BH); 1689sbr
(C=O); 1596m (C=C + C=N); 540s, 516s, 433m, (Ar3P); 302w. ESIMS (CH3OH): (−) 305 (55)
[PPh2(2-C6H4COO)]−, 417 (100) [Cu2Cl{TpMe}–H+]−, 623 (40) [Cu{PPh2(4-C6H4COO)}TpMe]−.
ESIMS
(CH3OH):
(+)
543
(100)
[Cu{PPh2(4-C6H4COOH)}TpMe–(PzMe)]+,
575
(15)
[Cu(TpMe)2 + 2H+]+, 625 (40) [Cu{PPh2(4-C6H4COOH)TpMe + H+]+, 701 (15) [Cu3(TpMe)2]+. Anal.
Calc. for C31H31BCuN6O2P: C, 59.6; H, 5.0; N, 13.4. Found: C, 60.0; H, 4.7; N, 14.0%.
61
1.7. {Cu[PPh2(4-C6H4COOH)]2pzTp} (5)
Compound 5 was prepared similarly to compound 1, by using CuCl (0.099 g, 1.0 mmol), [PPh2(4C6H4COOH] (0.613 g, 2.0 mmol) and K(pzTp) (0.318 g, 1.0 mmol) in CH3CN/methanol (1:2) solution.
Re-crystallization from CHCl3/diethyl ether (1:3) gave complex 5 as a micro-crystalline solid in 80%
yield, m.p.: 118 °C. 1H NMR (CDCl3, 293 K): δ 6.16 (t, 4H, 4-CH), 7.46 (d, 4H, 5-CH), 7.91 (d, 4H, 3CH), 7.20–7.40 (m, 28H, CH).
31
P{1H} NMR (CDCl3, 293 K): δ −0.2 (sbr);
31
P{1H} NMR (CDCl3,
218 K): δ −4.5 (br). IR (nujol, cm−1): 3110w, 3061w (CH), 1690sbr (C=O), 1594m (C=C + C=N),
531s, 508s, 443m, (Ar3P); 362m 296w, 261w. ESIMS (CH3OH): (−) 377 (100) [CuCl{pzTp}]−, 477
(20) [Cu2Cl2{pzTp}]−, 621 (60) [Cu{pzTp}2]−, 721 (30) [Cu2Cl{pzTp}2]−. ESIMS (CH3OH): (+) 649
(100) [Cu{PPh2(4-C6H4COOH)}pzTp + H+]+, 1019 (50) [Cu2{PPh2(4-C6H4COOH)}2pzTp]+. Anal.
Calc. for C50H42BCuN8O4P2: C, 62.9; H, 4.4; N, 11.7. Found: C, 63.0; H, 4.7; N, 12.0%.
1.8. {Cu[PPh2(4-C6H4COOH)]2pzTpMe} (6)
Compound 6 was prepared similarly to compound 1, by using CuCl (0.099 g, 1.0 mmol), [PPh2(4C6H4COOH] (0.613 g, 2.0 mmol) and K(pzTpMe) (0.374 g, 1.0 mmol) in CH3CN/methanol (1:2)
solution. Re-crystallization from CHCl3/diethyl ether (1:3) gave complex 5 as a micro-crystalline solid
in 74% yield, m.p.: 185 °C. 1H NMR (CDCl3, 293 K): δ 1.95 (s, 12H, 3-CCH3), 5.90 (d, 4H, 4-CH),
7.40 (d, 4H, 5-CH), 7.42–7.60 (m, 28H, CH).
31
P{1H} NMR (CDCl3, 293 K): δ 4.7 (sbr);
31
P{1H}
NMR (CDCl3, 218 K): δ −1.2 (sbr), 5.2 (sbr), 32.5 (s). IR (nujol, cm−1): 3050w (CH); 1703sbr (C=O);
1594m, 1520s (C=C + C=N); 543s, 521s, 491m, 420m, (Ar3P); 294w, 247w. ESIMS (CH3OH): (−) 433
(100) [CuCl{pzTpMe}]−, 533 (20) [CuCl{pzTpMe}(CuCl)]−, 731 (20) [CuCl{pzTpMe}(CuCl)3]−, 830
(20)
[CuCl{pzTpMe}(CuCl)4]−.
ESIMS
(CH3OH):
(+)
705
(100)
[Cu{PPh2(4-
C6H4COOH)}pzTpMe + H+]+, 1075 (50) [Cu2{PPh2(4-C6H4COOH)}2pzTpMe]+. Anal. Calc. for
C54H50BCuN8O4P2: C, 64.1; H, 5.0; N, 11.1. Found: C, 64.5; H, 4.7; N, 11.4%.
1.9. {Cu[PPh2(4-C6H4COOH)]2H2B(im)2} (7)
Compound 7 was prepared similarly to compound 1, by using CuCl (0.099 g, 1.0 mmol), [PPh2(4C6H4COOH] (0.613 g, 2.0 mmol) and [K{H2B(im)2} · (dmac)] (0.273 g, 1 mmol) in CH3CN/methanol
(1:2) solution. Re-crystallization from CHCl3/diethyl ether (1:3) gave complex 7 as a micro-crystalline
solid in 84% yield, m.p.: 300 °C. 1H NMR (DMSO, 293 K): δ 6.93 (s, 2H, 4- or 5-CH), 7.08 (s, 2H, 4or 5-CH), 7.30–7.95 (m, 30H, 2-CH and Ph). 31P{1H} NMR (DMSO, 293 K): δ −4.4 (sbr). IR (nujol,
62
cm−1): 3130w, 3041w (CH); 2402m (BH); 1690s (C=O); 1589m, 1536s (C=C + C=N); 533s, 510s,
489m, 441m, (Ar3P); 377m 302w. ESIMS (CH3OH): (−) 147 (100) [H2B(im)2]−, 245 (50)
[CuCl{H2B(im)2}]−, 305 (60) [PPh2(4-C6H4COO)]−, 515 (40) [Cu{H2B(im)2}{PPh2(4-C6H4COO)}]−,
673 (20) [Cu{PPh2(4-C6H4COO)}2]−. ESIMS (CH3OH): (+) 150 (100) [Cu(dmac)]+. Anal. Calc. for
C44H38BCuN4O4P2: C, 64.2; H, 4.6; N, 6.8. Found: C, 64.4; H, 4.2; N, 6.6%.
2. Results and discussion
The interaction between 4-(diphenylphosphane)benzoic acid, PPh2(p-C6H4COOH) (Fig. 23(a)), or 2(diphenylphosphane)benzoic acid (Fig. 23(b)), copper chloride and various MTp# ligands: KH2B(btz)2,
KHB(btz)3, NaTpMe, K(pzTp), KpzTpMe and KH2B(im)2(dmac) (Fig. 23(c)–(h)), in acetonitrile and
methanol solution at room temperature, readily gives complexes 1–7 in good yields, in accordance with
the following general equation (1).
M[Tp#]+CuCl+2PPh2(x-C6H4CO2H)→{Cu(PPh2(x-C6H4COOH)n(Tp#)}+MCl
(1)
63
Fig. 23. Structure of the P- and N-donor ligands employed in this work: (a) PPh2(p-C6H4COOH); (b) PPh2(o-C6H4COOH);
(c) [H2B(btz)2]−; (d) [HB(btz)3]−; (e) TpMe (=[HB(3-Mepz)3]−); (f) pzTp (=[B(pz)4]−); (g) pzTpMe (=[B(3-MePz)4]−); (h)
[H2B(im)2]−(dmac).
The 1:1 adducts 3 and 4 have been obtained even when large excess of phosphane ligand was
employed. Analogously, only 2:1 adducts 1, 2 and 5–7 have been obtained even when 1:1
stoichiometric ratio of phosphane-to-metal was employed; generally, the stoichiometry of this kind of
complexes is essentially independent on the ligand-to-metal ratio employed. In all cases, the excess of
phosphane ligand is necessary to avoid the copper oxidation.
With exception of compound 7, all the colourless compounds 1–6 are soluble in chlorinated or protic
solvents and air stable even as solutions. They are non-electrolytes in acetone or dichloromethane
solutions in which a non-ionic dissociation is likely, also on the basis of the
31
P{1H} NMR variable
temperature study (see below).
The infrared spectra show all the bands required by the presence of the nitrogen donor and the
phosphane ligand. For derivatives 1–4 and 7, the BH stretchings appear as a single or broad peak in the
expected regions. Upon coordination, these bands are slightly shifted to higher frequency with respect
to the same absorptions observed for the free ligands.
The broad absorptions from 1670 to 1690 cm−1 due to the carboxylic asymmetric stretching are slightly
shifted to smaller wave numbers with respect to the same absorptions observed for the free phosphane
64
ligands; this is likely due to the intermolecular hydrogen-bonding interactions, in the solid state,
between the carboxylic groups, as recently observed for analogous compounds of scorpionate ligands.
In the far-IR spectra of all derivatives, we have assigned, on the basis of previous reports on free
phosphanes282 and phosphane copper(I) complexes, the broad absorptions from 400 to 550 cm−1 to the
phenyl quadrant out of plane bending and in plane bending.283 In the far-IR region weak or medium
bands in the range 300–350 cm−1 appeared, similar to those described for copper-azolato complexes,
which are tentatively assigned to ν(Cu–N) stretching vibrations.259
The 1H NMR spectra, at 298 K, of compounds 1–7 exhibit only one set of signals for the protons of the
azolyl groups, suggesting highly fluxional species with either a rocking motion of the phosphane
copper(I) moiety between the two or three nitrogen atoms of the poly(azolyl)borate ligands or complete
dissociation and re-association of the azolyl nitrogens, which occur rapidly even at low temperature. In
fact, on cooling the CDCl3 or methanol solutions of selected samples, no additional signal appeared.
The room temperature
31
P NMR spectra of complexes 1–7 show a single resonance. A variable-
temperature 31P NMR study was performed from 293 to 218 K, in approximately 10 K decrements. The
room temperature 31P NMR spectra of complex 1 in chloroform solution exhibits a slightly broadened
signal (without multiplicity) centred at −3.6 ppm, compared with the sharp singlet at −4.8 ppm
exhibited by uncoordinated 4-(diphenylphosphane)benzoic acid; no signal due to oxidized form was
detected. The variable temperature
31
P NMR study of complex 1 shows sharp additional signals at
−1.4, −4.5 and 34.8 ppm, consistent with the occurrence of equilibria259 such as (2) and (3):
[Cu(R3P)n(Tp#)]
[Cu(R3P)n−1(Tp#)]+PR3
(2)
2[Cu(R3P)(Tp#)]
[Cu(Tp#)]2+2PR3
(3)
where the signal at 34.8 ppm is assignable to the oxidized form of the free phosphane coligand. An
analogous pattern has been observed in the variable temperature 31P NMR study of complexes 3–6. As
previously observed, the magnitude of Δ (= δ
31
Pcomplex − δ
31
Pfree ligand) is dependent on the
stoichiometric ratio N:M:P.246 In the present work, the δ31P for compounds 3 and 4, containing one
phosphane ligand for copper atom, are in the range 4.6–5.0 ppm (at 218 K), whereas the smaller values
of δ31P have been observed for derivatives 5 and 6 (−0.2 and −1.2 ppm, respectively, at 218 K),
indicating the presence of species in solution with two phosphane ligands coordinated to the metal
centre. The room temperature
31
P NMR spectrum of complex 2, in chloroform solution, exhibits a
65
slightly broadened signal (without multiplicity) centred at 1.3 ppm, compared with the sharp singlet at
−3.7 ppm exhibited by the uncoordinated 2-(diphenylphosphane)benzoic acid. The variable
temperature 31P NMR study of complex 2 shows no additional signals.
Analytical and spectroscopical data of compounds 1–6 are in accordance with four-coordinate species
with a N2CuP2 core (derivatives 1, 2, 5 and 6) or N3CuP core (derivatives 3 and 4); for compound 7 we
propose a dimeric or polymeric species in which the [H2B(im)2]− ligand coordinates in bridging
bidentate mode with a N2CuP2 core, as previously reported for analogous silver(I) complexes.
Electrospray ionization mass spectroscopy (ESI-MS) has emerged as a technique for investigation of
solution aggregations of covalent and noncovalent species. ESI-MS is able to transfer ionized analyte
species in solution into the gas phase by non-energetic processes that efficiently deliver intact entities
to the mass analyzer.284 In the case of coordination polymers, ESI-MS was used to probe the
aggregation between the ligands and silver(I) salts in solution, aggregates that might be related to the
building blocks and subsequently to the final supramolecular structure of the coordination polymers.285
By varying conditions in the electrospray interface, however, collision-induced dissociation may occur,
resulting in fragmentation of the parent ion, which in turn can provide some structural information
about the analite. In the present work, ESI-MS was used to probe the existence of aggregates of 4(diphenylphosphane)benzoic acid or 2-(diphenylphosphane)benzoic acid and scorpionate ligands with
copper(I) in solution.
Both positive-ion and negative-ion spectra of derivatives 1–7 dissolved in methanol were recorded at
low fragmentor voltage; in these conditions, the dissociation is minimal and a high proportion of the
analyte is transported to the mass spectrometer as the intact molecular species.
The positive-ion spectrum of 1 in methanol is dominated by a fragment at m/z 675 (100%) attributable
to [Cu{PPh2(p-C6H4COOH)}2]+ species and due to the ligand [H2B(btz)2]− loss from 1. The ions
[H2B(btz)2]− (m/z 249, 100%) and [CuCl{H2B(btz)2}]− (m/z 347, 40%) dominate the negative-ion ESIMS spectrum.
The positive-ion spectra of compounds 5 and 6 are dominated by the protonated species [Cu{PPh2(4C6H4COOH)}pzTp + H+]+ (m/z 649, 100%) and [Cu{PPh2(4-C6H4COOH)}pzTp + H+]+ (m/z 705,
100%), respectively. Only minor ions at m/z 1019 (50%) and m/z 1075 (50%), attributable to the
[Cu2PPh2(4-C6H4COOH)}2pzTpMe]+ and [Cu2{PPh2(4-C6H4COOH)}2pzTp]+ species, respectively, can
be identified in the positive-ion spectra. The relevant peaks in the negative-ion spectra of compounds 5
and 6 are attributable to the species [CuCl{pzTp}]− (m/z 377, 100%) and [CuCl{pzTpMe}]− (m/z 434,
100%), respectively. Some more peaks due to the aggregates of copper(I) with scorpionate (Tp#) and
66
phosphane ligands have also been detected and identified by the characteristic isotope distribution
patterns (see Section 2).
The positive-ion spectrum of compound 4 shows a major peak at m/z 543 (100%), possibly due to the
{Cu[PPh2(4-C6H4COOH)}TpMe–(PzMe)]+ species, derived from the loss of one 3-methylpyrazolate
from the monomeric complex [Cu{PPh2(4-C6H4COOH)}TpMe + H+]+, observed at m/z 625 (40%). In
the negative-ion spectrum of derivative 4, the major peaks are those attributable to the deprotonated
phosphane [PPh2(p-C6H4COO)]− at m/z 305 (55%), to the {Cu[PPh2(4-C6H4COO)}TpMe]− complex at
m/z 623 (40%) and to the aggregate of copper(I) and chloride with the TpMe ligand, [Cu2Cl{TpMe}–
H+]−, at m/z 417 (100%). A similar trend was observed for compounds 2 and 3; in fact, the positive-ion
spectra show, respectively, major peaks at m/z 675 (100%, compound 2) and at m/z 711 (100%,
compound 3) assignable to the [Cu{PPh2(2-C6H4COOH)}2]+ and [CuCl{PPh2(4-C6H4COOH)}2 + H+]+
species, respectively. In the negative-ion spectra of derivatives 2 and 3, the major peaks are those of
scorpionate ligands, [H2B(btz)2]− and [HB(btz)3]−, at m/z 249 (100%) and at m/z 366 (100%),
respectively. For compound 7 the poor solubility in methanol solution is, however, sufficient to identify
in the positive-ion spectrum the species [Cu(dmac)]+ at m/z 150 (100%), and in the negative-ion
spectrum the majority species at m/z 147 (100%) due to [H2B(Im)2]− ligand, at m/z 245 (50%) due to
[CuCl{H2B(Im)2}]− species and at m/z 305 (60%) due to the [PPh2(4-C6H4COO)]− phosphane coligand.
An evidence of these species is also available from 31P{1H} NMR investigation (see above); however,
it is worth noting that the NMR spectra consist of a single phosphorus resonance due to a mixture of
species in rapid equilibrium. Finally, there was no evidence in both positive- and negative-ion spectra
of derivatives 1–7 of phosphane oxide and related copper(I) complexes.
ESI-MS measurements in the positive ion mode appear to privilege the collection of copper-phosphane
species, while measurements in the negative ion mode show mostly fragment ions including Cu–N
scorpionate molecules; this behaviour can be due to the formation of stable copper-phosphane
complexes and to the monoanionic nature of the ligands.286,287
These new copper(I) complexes have been studied by using chemiluminescence assay in order to assess
their eventual antioxidant activity as superoxide anion scavengers. In fact, it is known that superoxide
anion is one of the reactive oxygen species responsible for many diseases associated with the stress
oxidative conditions. Chemiluminescence determinations were performed by using lucigenin as
chemiluminogenic probe for superoxide radical produced by xanthine/xanthine oxidase system. The
reaction of lucigenin with superoxide radical gives rise to chemiluminescence and the level of CL
indicates the presence of superoxide in the medium under study.288 Fig. 24 shows the per cent of
67
inhibition of the lucigenin amplified chemiluminescence signal measured in the presence of copper(I)
complexes 1–7 and, as references, in the presence of enzyme superoxide dismutase and nitroxide
Tempo.
Fig. 24. Inhibition (%) of lucigenin-amplified chemiluminescence of the xanthine/xanthine oxidase system in the presence
of superoxide dismutase, Tempo and the copper(I) complexes. Chemiluminescence was measured in the presence of
0.9U/ml xanthine oxidase and 150 μM lucigenin; the reaction was initiated by injecting xanthine at a final concentration of
50 μM in Tris 50 mM, pH 7.4 buffer. Inhibition values refer to peak heights. (♦) 1; (▪) 2; (
) 3; ( ) 4; (*) 5; (•) 6; ( ) 7;
()Tempo; ( ) SOD.
Superoxide dismutase is the enzyme that eliminates superoxide anion; the complete inhibition of CL
signal is obtained with less than 0.05 μM of enzyme. Tempo, a nitroxide radical known for its capacity
to mimic superoxide dismutase, compared to the other complexes, shows a low activity. The copper(I)
complexes are all able to reduce the superoxide level except for the complex 4 that reduces the CL
signal no more than 30% at every concentration tested. The concentration of sample, that induces 50%
inhibition of CL peak, was 0.6 μM for complex 2 and 1.6 μM for complex 7. The other copper (I)
complexes showed about the same activity; the 50% of CL signal inhibition was obtained by adding to
the reaction mixture 4, 4.6 and 3.3 μM of compounds 3, 5 and 6, respectively.
In conclusion, our results show that these new copper(I) complexes have “in vitro” an antioxidant
activity towards superoxide anion. These preliminary data need further investigations in order to better
68
understand the antioxidant capacity of these complexes and their potential use in mitigating the
deleterious effects exerted by reactive oxygen species to biological systems.
69
Chapter 3
Synthesis, characterization and antioxidant activity
of new copper(I) complexes of scorpionate and water
soluble phosphane ligands
In this session, it will be described the synthesis and the spectroscopic and analytical characterization
of new tris(4-bromopyrazol-1-yl)borate, bis(3,5-dimethylpyrazol-1-yl)acetate and tris(pyrazol-1yl)methanesulfonate complexes containing copper(I) and the 4- or 2-(diphenylphosphane)benzoic acid
or tris(m-sulfonatophenyl)posphine trisodium salt (TPPTS = Na3[P(C6H4-m-SO3)3])279 coligands. The
X-ray crystal structure of {Cu[PPh2(4-C6H4COOH)](Tp4Br)} shows an array of unusual supramolecular
structure supported by a multitude of non-covalent interaction, such as secondary O–H O hydrogen
bonds, C–H H–B weak dihydrogen bonds and the other C–H
interactions.289
We tested the superoxide scavenging activity of these new copper complexes, as seen in Chapter 2, by
a chemiluminescence (CL) technique, using lucigenin as chemiluminogenic probe sensitive to
superoxide anion produced by the xanthine/xanthine oxidase system.280 The antioxidant activity of
these complexes has been compared with the enzyme superoxide dismutase (this enzyme catalyzes the
dismutation reaction of superoxide anion), with the nitroxide radical TEMPO, a compound known to
possess SOD-mimic activity281 and with Cu2(aspirinate)4 a well-known copper(II) drug studied for its
anti-inflammatory activity.
To further explore the antioxidant role of these compounds in connection with the effects of nitric
oxide and RNOS (reactive nitrogen oxide species) in biological systems, we evaluated their possible
protective role in mitigating DNA oxidative damage in rat epithelial cells. Nitric oxide (NO) has been
implicated in a variety of different diseases.290 One of the reasons why NO is presumably toxic is due
to its reaction with oxygen or the superoxide anion which leads directly to genotoxicity, mediated by
N2O3 and peroxynitrite. DNA damage was induced by S-nitrosoglutathione monoethyl ester (GSNOMEE), a nitric oxide donor,291 Angeli's salt (N2O3) a common nitroxyl anion donor,292 and SIN-1 (3-
70
morpholino-sydnonimine) a peroxynitrite generating agent.293 For this research, rat trachea epithelial
cells were chosen as a biological model and exposed under aerobic conditions to the compounds above
in the absence and presence of the new Cu(I) complexes. DNA damage was assessed using the Comet
assay, a rapid and sensitive, single-gel electrophoresis technique used to detect primary DNA damage
in individual cells.294
1. Experimental section
1.1. Material and methods
All syntheses and handling were carried out under an atmosphere of dry oxygen-free dinitrogen, using
standard Schlenk techniques or a glove box. All solvents were dried, degassed and distilled prior to use.
Elemental analyses (C,H,N,S) were performed in-house with a Fisons Instruments 1108 CHNS-O
Elemental Analyser. IR spectra were recorded from 4000 to 100 cm–1 with a Perkin-Elmer System
2000 FT-IR instrument. 1H-, and 31P-NMR spectra were recorded on a VXR-300 Varian spectrometer
(300 MHz for 1H, and 121.4 MHz for
31
P). Electrospray mass spectra were obtained in positive- or
negative-ion mode on a Series 1100 MSD detector HP spectrometer, using a methanol mobile phase.
The compounds were added to the reagent grade methanol to give solutions of 0.1 mM concentration.
These solutions were injected (1 µl) into the spectrometer via a HPLC HP 1090 Series II fitted with an
autosampler. The pump delivered the solutions to the mass spectrometer source at a flow rate of 300 µl
min–1, and nitrogen was employed as both a drying and nebulizing gas. Capillary voltages were
typically 4000 V and 3500 V for positive- and negative-ion modes, respectively. Confirmation of all
major species in this ESI-MS study was aided by comparison of the observed and predicted isotope
distribution patterns, the latter calculated using the IsoPro computer program.
1.2. Syntheses
All reagents were purchased from Aldrich and used without further purification. The potassium
hydrotris(4-bromo-1H-pyrazol-1-yl)borate, KTp4Br,295 the lithium salt of bis(3,5-dimethylpyrazol-1yl)acetate Li[L2CO2]296 and the lithium salt of tris(pyrazol-1-yl)methanesulfonate Li(Tpms)138 were
synthesised
in
accordance
with
literature
methods.
The
coligands
4-
or
2-
(diphenylphosphane)benzoic297 and tris(m-sulfonatophenyl)posphine trisodium salt (TPPTS)298 was
prepared according to published procedures.
71
1.3. {Cu[PPh2(4-C6H4COOH)](Tp4Br)}(1)
To a CH3OH/CH3CN (1/1) solution (50 ml) of CuCl (0.099 g, 1.0 mmol) and [PPh 2(4-C6H4COOH]
(0.612 g, 2.0 mmol), KTp4Br (0.488 g, 1.0 mmol) was added at room temperature. After the addition,
the solution was stirred for 5 h and the solvent subsequently removed with a rotary evaporator. CHCl3
(50 ml) was added; the suspension was filtered and concentrated under reduced pressure. A colorless
precipitate was formed, which was filtered off and washed with diethyl ether. Re-crystallization from
diethyl ether/n-hexane 1/3 gave complex 1 as a microcrystalline solid in 64% yield. M.p.: 202–206 °C.
1
H NMR (CDCl3, 293 K): 7.16 (s, 3H, 5-CH), 7.50–7.78 (m, 12H, CH), 7.88 (s, 3H, 3-CH), 8.19 (dd,
2H, CH).
31
P{1H} NMR (CDCl3, 293 K): 6.7 (sbr);
31
P{1H} NMR (CDCl3, 223 K): 6.2 (s). IR
(nujol, cm–1): 3122w (C–H); 2474mbr (B–H); 1680sbr (C O); 1594m, 1557m (C C + C N); 542s,
516s, 494s, 412m (PAr3); 372m, 318mbr (Cu–N). ESI-MS (CH3OH): (–) 817 (100) [{HB(4BrPz)3}Cu{PPh2(4-C6H4COO)}]–, 548 (40) [CuCl{HB(4-BrPz)3}]–, 450 (30) [HB(4-BrPz)3]–, 305 (30)
[PPh2(4-C6H4COO)]–. Calcd. for C28H22BBr3CuN6O2P; C, 41.04; H; 2.71; N, 10.25. Found: C, 41.30;
H; 2.58; N, 10.35%.
1.4. {Cu[PPh2(2-C6H4COOH)](Tp4Br)}(2)
Compound 2 was prepared similarly to compound 1, by using CuCl (0.099 g, 1.0 mmol), [PPh2(2C6H4COOH] (0.612 g, 2.0 mmol) and KTp4Br (0.488 g, 1.0 mmol) in CH3OH/CH3CN (1/1) solution.
Re-crystallisation from methanol/n-hexane (1 5) gave complex 2 as a micro-crystalline solid in 76%
yield. M.p.: 122 °C dec. 1H NMR (CDCl3, 293 K): 7.09 (s, 3H, 5-CH), 7.20–7.50 (m, 12H, CH), 7.58
(s, 3H, 3-CH), 8.16 (dd, 2H, CH).
31
P{1H} NMR (CDCl3, 293 K): 0.2 (br);
31
P{1H} NMR (CDCl3,
223 K): –0.5 (s), 2.6 (s), 37.3 (s). IR (nujol, cm–1): 3183w, 3124w (C–H); 2464mbr (B–H); 1702mbr
(C O); 1586w (C C + C N); 547w, 535s, 525w, 505mbr, 496mbr (PAr3); 376w, 315mw (Cu–N). ESIMS (CH3OH): (–) 450 (60) [HB(4-BrPz)3]–, 548 (100) [CuCl{HB(4-BrPz)3}]–, 305 (50) [PPh2(2C6H4COO)]–, 962 (40) [Cu{HB(4-BrPz)3}2]–. ESI-MS (CH3OH): (+) 361 (100) [Na(CH3OH){PPh2(2C6H4COOH)}]+,
676
(50)
[Cu{PPh2(2-C6H4COOH)}2]+,
858
(20)
[Cu(K){PPh2(2-
C6H4COOH)}{HB(4-BrPz)3}]+, 1081 (40) [Cu4Cl2{PPh2(2-C6H4COOH)}{HB(4-BrPz)3}]+. Calcd. for
C28H22BBr3CuN6O2P; C, 41.04; H; 2.71; N, 10.25. Found: C, 40.82; H; 2.61; N, 10.13%.
72
1.5. {Cu[PPh2(4-C6H4COOH)]2(L2CO2)}(3)
To a CH3OH/CH3CN (1/1) solution (50 ml) of CuCl (0.099 g, 1.0 mmol) and [PPh 2(4-C6H4COOH]
(0.612 g, 2.0 mmol), Li[L2CO2]·H2O (0.272 g, 1.0 mmol) was added at room temperature. After the
addition, the solution was stirred for 5 h and the solvent subsequently removed with a rotary
evaporator. CHCl3 (50 ml) was added; the suspension was filtered and concentrated under reduced
pressure. A colorless precipitate was formed, which was filtered off and washed with diethyl ether. Recrystallization from CHCl3/diethyl ether 1/5 gave complex 3 as a microcrystalline solid in 80% yield.
M.p.: 180 °C dec. 1H NMR (CD3OD, 293 K): 1.88 (s, 6H, 3-CH3), 2.48 (s, 6H, 5-CH3), 6.02 (s, 2H, 4CH), 6.63 (s, 1H, CH), 7.40 (mbr, 24H, CH), 7.91 (mbr, 4H, CH). 31P{1H} NMR (CD3OD, 293 K): –
3.3 (sbr);
31
P{1H} NMR (CD3OD, 223 K): –4.0 (sbr), –2.5 (s), 3.9 (sbr), 33.8 (s). IR (nujol, cm–1):
3172w, 3055w (C–H); 1690sh, 1654sbr (C O); 1597m, 1558m (C C + C N); 532s, 511s, 491wbr
(PAr3); 399w, 352w (Cu–N). ESI-MS (CH3OH): (–) 305 (100) [PPh2(4-C6H4COO)]–, 615 (40)
[(L2CO2)Cu{PPh2(4-C6H4COO)}]–. ESI-MS (CH3OH): (+) 71 (100) [Li(CH3OH)2]+, 618 (20)
[(L2CO2)Cu{PPh2(4-C6H4COOH)} + H+]+, 770 (90) [Cu2(CH3OH){PPh2(4-C6H4COO)}2 + H+]+.
Calcd. for C50H45CuN4O6P2; C, 65.04; H; 4.91; N, 6.07. Found: C, 65.23; H; 5.01; N, 6.24%.
1.6. {Cu[TPPTS](Tpms)}(4)
To a CH3OH/CH3CN (1/2) solution (50 ml) of [Cu(CH3CN)4]PF6 (0.097 g, 0.262 mmol), Na3[P(C6H4m-SO3)3] (0.298 g, 0.524 mmol) was added at room temperature. After the addition, the solution was
stirred for 12 h and subsequently Li(Tpms) (0.081 g, 0.262 mmol) was added at room temperature.
After 2 h the suspension was filtered and concentrated under reduced pressure. Re-crystallization from
CHCl3/n-hexane 1/5 gave complex 4 as a microcrystalline solid in 65% yield. M.p.: 300 °C dec. 1H
NMR (CD3OD, 293 K): 6.45 (t, 3H, 4-CH), 7.46–7.94 (mc, 12H, CH), 7.75 (d, 3H, 5-CH), 8.16 (d,
3H, 3-CH). 31P{1H} NMR (CD3OD, 293 K): –1.6 (br), 30.7 (s); 31P{1H} NMR (CD3OD, 223 K): –
4.9 (s), –1.6 (s), 8.4 (s), 30.7 (s). IR (nujol, cm–1): 3159w, 3092w (C–H); 1650w; 1520w, (C C + C
N); 1188w, 1149m, 1101m, 1041m, 624s, 610s, 557s, 525s, 492wbr (SO3 and PAr3); 384w, 322w (Cu–
N). ESI-MS (CH3OH): (–) 166 (100) [TPPTS – 3 Na+]3–, 261 (70) [TPPTS – 2Na+]2–, 281 (90) [TPPTS
– 3Na+ + Cu+]2–, 293 (100) [Tpms]–, 431 (30) [Cu(TPPTS)(Tpms) – 3Na+ + Li+]2–, 545 (30) [TPPTS –
Na+]–. Calcd. for C28H21CuN6Na3O12PS4; C, 36.35; H; 2.29; N, 9.08; S, 13.86. Found: C, 36.45; H;
2.41; N, 9.24; S, 14.02%.
73
1.7. Chemiluminescence assay
All reagents used were of pure analytical grade. Xanthine, xanthine oxidase (E.C. 1.1.3.22) and
superoxide dismutase (E.C. 1.15.1.1) were from bovine erythrocytes, TEMPO and lucigenin were
obtained from Sigma Chemical Co., St. Louis, MO.
Chemiluminescence measurements were performed using lucigenin as chemiluminogenic probe, and
superoxide radical was produced by the xanthine/xanthine oxidase system. The chemiluminescence
(CL) was measured in Autolumat LB953 (Berthold Co. Wildbad, Germany) in a reaction mixture
containing 0.9 U ml–1 xanthine oxidase, 150 µM lucigenin in Tris 50 mM pH 7.4 buffer and different
concentrations of compounds dissolved in ethanol. The reaction was started by injecting xanthine at a
final concentration of 50 µM. Lucigenin-amplified CL, produced by superoxide anion and generated
from the xanthine/xanthine oxidase system, showed a peak value at
reaction (injection of xanthine); the reaction was terminated after
10 s. after initiation of the
40 s. The peak value indicated the
presence of O2– in the medium. It was due to light emission (photons) during the reaction that was
revealed by a chemiluminescence detector as counts per second (cps). Data refer to at least three
individual experiments.
1.8. Cell preparation and treatment
The epithelial cells used in this study were isolated from the trachea of Wistar rats of both sexes
(Charles River, Calco, Italy). Routinely, the rat was killed after exposure to CO2 for 20 s and the
trachea surgically removed and placed in MEM (37 °C) containing 400 U collagenase type IV ml –1 for
10 min. Thereafter, the epithelium of the inner surface of the trachea was carefully scraped off with a
small lancet and incubated for 30 min in the same MEM as above at 37 °C. The resulting suspension
was carefully filtered through four layers of sterile gauze and centrifuged for 10 min at 3000 rpm. The
cell pellet was then suspended in phosphate buffered saline (PBS) for the determination of cell number
and viability. The epithelial cells (1 × 106 cells ml–1), isolated as described above, were placed into
Eppendorf tubes and incubated for 20 min at 37 °C in the presence or absence of final concentrations of
150 µM GSNO-MEE dissolved in PBS, or 200 µM Angeli's salt or 1 mM SIN-1 all dissolved in 10
mM NaOH, and in the presence or absence of 5 or 10 µM copper(I) complexes dissolved in ethanol
(maximum volume 1%). Finally, after incubation, the samples were centrifuged (3000 rpm for 3 min)
and analysed.
This study was approved by the Joint Ethical Committee University of Camerino and A.S.L 10 of
Camerino, prot. n.4/2004, accordingly to art.2 of the University of Camerino Statute.
74
1.9. Comet assay
The Comet assay used to measure the DNA strand breaks in individual cells was essentially the same
as described previously.299 Cells were suspended in 0.7% low melting agarose in PBS and pipetted on
microscope slides pre-coated with a layer of 1% normal melting agarose. The agarose with the cell
suspension was allowed to set on the pre-coated slides at 4 °C for 10 min. Subsequently, another top
layer of 0.7% low melting agarose was added and allowed to set at 4 °C for 10 min. The slides were
then immersed in lysis solution (1% sodium n-lauroyl-sarcosinate, 2.5 M NaCl, 100 mM Na2EDTA, 10
mM Tris HCl pH 10, 1% Triton X-100 and 10% DMSO) for 1 h at 4 °C in the dark in order to lyse the
embedded cells and to permit DNA unfolding. After incubation in lysis solution, slides were exposed to
alkaline buffer (1 mM Na2EDTA, 300 mM NaOH buffer, pH >13) for 20 min; in this condition RNA is
completely degraded. The slides were subjected to 20 min electrophoresis at 25 V in the same alkaline
buffer. The slides were finally washed with 0.4 M Tris HCl buffer (pH 7.5) to neutralise excess alkali
and to remove detergents before staining with ethidium bromide (2 µg ml–1).
Cells were examined with an Axioskop 2 plus microscope (Carl Zeiss, Germany) equipped with an
excitation filter of 515–560 nm and a magnification of ×20. Imaging was performed using a specialised
analysis system ( Metasystem Altlussheim, Germany) to determine tail length, tail intensity and tail
moment (TL, TI and TM)—all parameters correlated with the degree of DNA damage in the single
cells. Statistical comparisons were performed using the student t-test and differences were regarded as
statistically significant when p values were <.05 (*), <.01 (**), <.001 (***).
1.10. X-ray crystallography
The crude complex {Cu[PPh2(4-C6H4COOH)](Tp4Br)}, 1, was dissolved in a chloroform/hexane
solution; a single crystal suitable for X-ray diffraction analysis was obtained and mounted on a Rigaku
AFC5R diffractometer using graphite-monochromatized Cu-K radiation (1.54178
anode generator. The crystals are monoclinic, a = 12.595(3)
91.15(2)°, V = 3500(1)
3
, b = 20.775(5)
) and a rotating
, c = 13.381(3)
, =
, T = 296 K, space group P21/n (no. 14), Z = 4, µ(Cu-K ) = 6.1 mm–1, 5599
reflections measured, 5531 unique (Rint = 0.053), 2604 observed (I > 3 (I)) were used in all
calculations. The final R(F) and wR(F2) were 0.055 and 0.073, respectively. The cell parameters were
refined by least squares from the angular positions of 18 reflections in the range 62.77° < 2 < 72.61°.
The data were measured at room temperature for 6.6° < 2 < 124.16° using a /2 scan technique. The
data were processed to yield values of I and
(I) corrected for Lorentz, polarisation and shape
75
anisotropy effects. The observed reflections were processed by the direct methods program SIR2002,300
which provided the complete structure. All non-hydrogen atoms were refined by a full-matrix least
squares method with anisotropic thermal parameters. The hydrogen atoms were idealised (C–H = 0.96
). Each H atom was assigned the equivalent isotropic temperature factor of the parent atom and
allowed to ride on it. The final difference Fourier map, with a root-mean-square deviation of electron
density of 0.08 e
–3
showed three peaks, one of them close to a centre of inversion. Attempts were
made to solve the disorder working on space groups with low symmetry Pn, but unsuccessfully.
Because the compound was crystallized from a chloroform/hexane solution, our calculations showed
that the peaks of the solvent molecule could be disordered hexane rather than chloroform. No other
peaks were found in the Fourier maps to give a model of disorder. Convergence was reached by
introducing the three peaks as carbon atoms into the refinement and the R index lowered from 0.073 to
0.055. Calculations were performed using the SIR2002 and CAOS structure determination packages.301
2. Results and discussion
2.1. Reaction stoichiometry and spectroscopic data
The interaction between 4-(diphenylphosphane)benzoic acid, PPh2(4-C6H4COOH) (Fig. 25a) or 2(diphenylphosphane)benzoic acid, PPh2(2-C6H4COOH) (Fig. 25b), copper chloride and the ligands,
potassium salt of tris(4-bromopirazol-1-yl)borate, KTp4Br (Fig. 25d) or lithium salt of bis(3,5dimethylpyrazol-1-yl)acetate Li[L2CO2] (Fig. 25e), in acetonitrile/methanol solution at room
temperature readily produces complexes 1–3 in good yields, in accordance with the following general
eq. (1).
ML + CuCl + 2 PPh2R
{Cu[PPh2R]n(L)} + MCl + (PPh2R)2 – n
(1)
1: ML = KTp4Br; R = (4-C6H4COOH); n = 1
2: ML = KTp4Br; R = (2-C6H4COOH); n = 1
3: ML = Li[L2CO2]; R = (4-C6H4COOH); n = 2
76
Fig. 25. Structure of the P- and N-donor ligands employed in this work: (a) PPh2(4-C6H4COOH); (b) PPh2(2-C6H4COOH);
(c) TPPTS; (d)[HB(4-Brpz)3]–; (e)[L2CO2]–; (f) Tpms.
Analogously the adduct 4 has been obtained from the interaction of [Cu(CH3CN)4]PF6, TPPTS (Fig.
25c) and the ligand Li(Tpms) (Fig. 25f) in CH3OH/CH3CN solution at room temperature (eqn. (2)).
[Cu(CH3CN)4]PF6 + 2 TPPTS + Li(Tpms)
{Cu[TPPTS](Tpms)} + TPPTS + LiPF6
(2)
The stoichiometry of these kinds of complexes is essentially independent of the ligand-to-metal ratio
employed. In all cases the excess of phosphane ligand is necessary to avoid copper oxidation. All the
colourless compounds 1–4 are soluble in chlorinated or protic solvents and air stable even as solutions.
The infrared spectra show all the bands required by the presence of the nitrogen donor and the
phosphane ligand. For derivatives 1 and 2 the BH stretchings appear as single and broad peaks in the
expected regions (2474 and 2464 cm–1, respectively).263 Upon coordination these bands are slightly
shifted to higher frequency with respect to the same absorptions observed for the free ligands. For
derivatives 1–3 the broad absorptions from 1690 to 1704 cm–1 due to the carboxylic asymmetric
stretching are slightly shifted to smaller wave numbers with respect to the same absorptions observed
for the free phosphane ligands; this is likely to be due to the intermolecular hydrogen-bonding
interactions, in the solid state, between the carboxylic groups of phosphane ligands. In addition, the
infrared spectra of compound 3 shows an intense
–
as(CO2 )
absorption at 1654 cm–1 and medium
intensity bands at 1558 cm–1 due to (C N). These values fit those reported for analogous Zn and Fe
complexes.302 In the far-IR region, weak or medium bands in the 300–400 cm–1 range appeared, similar
to those described for copper–azolato complexes,259 which are tentatively assigned to
(Cu–N)
77
stretching vibrations. In the spectrum of compound 4 we observe in the 525–610 cm–1 range bands
attributable to deformation modes of the sulfonate group;303 at 1041 cm–1, a mode appears which
corresponds to a combination of phenyl stretching and bending modes with a SO3– asymmetric mode; a
stretching mode of SO3– seems to appear at 1188 cm–1.
The 1H NMR spectra at 298 K of compounds 1 and 2 in chloroform solution, exhibit only one set of
signals for the protons of the pyrazolyl groups, suggesting the presence in solution of C3v-symmetrical
complexes. The 1H NMR spectrum of compound 3 exhibits only one set of signals for the H(4) and
CH3 protons of the pyrazolyl groups, suggesting highly fluxional species even at low temperature. The
1
H NMR spectrum at 298 K of derivative 4, in methanol solution, shows one set of resonances for
H(3), H(5) and H(4), indicating that all pyrazole rings are equivalent. In addition, all the resonances are
shifted to lower field in comparison with those of the lithium salt Li(Tpms). Variable temperature
NMR studies have been performed for complex 4: it was possible to slow down the rate of the dynamic
process responsible for the spectrum obtained at room temperature; at 213 K only broad signals, but not
a static spectrum have been obtained.
The room temperature
31
P NMR spectra of complex 1, in chloroform solution, exhibits a broadened
signal centered at 6.7 ppm, compared with the sharp singlet at –4.8 ppm exhibited by uncoordinated 4(diphenylphosphane)benzoic acid; no signal due to the oxidized form was detected. The variable
temperature
31
temperature
31
P NMR study of complex 1 shows no additional signals or significant shifts. The room
P NMR spectra of complex 2, in chloroform solution, exhibits a broadened signal
centered at 0.2 ppm, compared with the sharp singlet at –3.7 ppm exhibited by uncoordinated 2(diphenylphosphane)benzoic acid. The variable temperature 31P NMR study of complex 2 shows sharp
additional signals at 2.6 ppm, consistent with the occurrence of equilibria such as (eqn. (3))
[Cu(PR3)n(L)]
[Cu(PR3)n – 1(L)] + PR3
(3)
and at 37.3 ppm, assignable to the oxidized form of the free phosphane coligand. 304 An analogous
pattern has been observed in the variable temperature
solution. The room temperature
31
31
P NMR study of complex 3, in CD3OD
P NMR spectrum of derivative 4, in methanol solution, exhibits a
broadened signal centered at –1.6 ppm, compared with the sharp singlet at –5.0 ppm exhibited by
uncoordinated TPPTS; no signal due to the oxidized form was detected. The
31
P NMR spectrum,
recorded at 218 K, shows additional signals at –4.9 and 8.4 ppm, indicating the presence in solution of
species with two or one phosphane ligands, respectively, coordinated to the metal centre.
78
Electrospray ionization mass spectroscopy (ESI-MS) has emerged as a technique for investigating
solution aggregation of covalent and non-covalent species. ESI-MS is able to transfer ionized analyte
species in solution into the gas phase by non-energetic processes that efficiently deliver intact entities
to the mass analyzer.284 In the present work ESI-MS was used to probe the existence of aggregates of
phosphane and scorpionate ligands with copper(I) in solution.
Both positive-ion and negative-ion spectra of derivatives 1–4 dissolved in methanol were recorded at
low fragmentor voltage; in these conditions the dissociation is minimal and a high proportion of the
analyte is transported to the mass spectrometer as the intact molecular species. The negative-ion spectra
of 1 and 2 in methanol are respectively dominated by a fragment at m/z 817 (100%) attributable to the
[{HB(4-BrPz)3}Cu{PPh2(4-C6H4COO)}]– species and by a fragment at m/z 548 (100%) attributable to
[CuCl{HB(4-BrPz)3}]–. The positive-ion spectrum of compound 2 is dominated by the adducts
[Na(CH3OH){PPh2(2-C6H4COOH)}]+ and [Cu{(PPh2(2-C6H4COOH)}2]+. In the positive-ion spectrum
of derivative 3 the major peaks are those attributable to [Li(CH3OH)2]+ at m/z 71 (100%) and to
[Cu2(CH3OH){PPh2(4-C6H4COO)}2 + H+]+ at m/z 770 (90%). In the same compound, the negative-ion
spectrum shows a peak due to the deprotonated phosphane carboxylic acid, [PPh2(4-C6H4COO)]–,
detected at m/z 305 (100%), together with a peak due to the aggregate of copper(I),
[(L2CO2)Cu{PPh2{4-C6H4COO)}]–, at m/z 615 (40%). No significant signals were detected in the
positive-ion spectra of compounds 1 and 4. On the other hand the negative-ion spectrum of compound
4 is very complicated and presents a variety of signals due to the multi-charge species as [TPPTS –
3Na+]3– (m/z 166, 100%), [TPPTS – 2Na+]2– (m/z 261, 70%), [TPMS – 3Na+ + Cu+]2– (m/z 281, 90%),
[Cu(TPPTS)(Tpms) – 3Na+ + Li+]2– (m/z 431, 30%). Finally, there was no evidence of derivatives 1–3
of phosphane oxide and related copper(I) complexes in both positive- and negative-ion spectra.
2.2. Structure determination
Single crystal structure determination was made for complex 1, consistent with its formulation in terms
of
stoichiometry
and
connectivity
as
an
adduct
of
the
form
{Cu[PPh 2(4-
C6H4COOH)](Tp4Br)}·(C6H14)0.5. The hexane molecule is modelled as disordered and presents only
non-covalent interactions with the complex.
Pertinent results are given in Table 2, Table 3 and in Fig. 26, the latter showing 50% probability
displacement envelopes for the non-hydrogen atoms.
79
Table 2 Selected geometries of {Cu[PPh2(4-C6H4COOH)](Tp4Br)}·(C6H14)0.5
Atom
Parameters
Distances/
Cu1–P1
2.158(3)
Cu1–N1
2.065(8)
Cu1–N3
2.063(9)
Cu1–N5
2.118(8)
Angles/°
P1–Cu1–N1
124.2(2)
P1–Cu1–N3
131.8(2)
P1–Cu1–N5
118.3(3)
N1–Cu1–N3
92.4(3)
N1–Cu1–N5
89.7(3)
N3–Cu1–N5
88.6(3)
Table 3 Contact distances of {Cu[PPh2(4-C6H4COOH)](Tp4Br)}·(C6H14)0.5
O1 O2a
2.62(1)
C29 H1b
2.71( 7)
H4 H21c
2.38( 2)
Symmetry code:a 2 – x, 1 – y, 1 – z
b
½ + x, ½ – y, z – ½
c
2 – x, –y, –z
80
Fig. 26. Molecular projection showing 50% displacement ellipsoids for the non-hydrogen atoms of {Cu[PPh2(4C6H4COOH)](Tp4Br)}·(C6H14)0.5.
The metal atom lying in a four-coordinate PCuN3 array, the PCu(Tp4Br) component of quasi-3m
symmetry, degraded to quasi-3 by the phosphorus substituents, which, relative to the pyrazole
components, are quasi-eclipsed. The geometry about the metal atom (Table 2) is comparable with those
recently recorded in analogous PCuN3 arrays (R3P)Cu(Tpx) systems (Tpx = poly(pyrazol-1yl)borates).160,246,255
The {Cu[PPh2(4-C6H4COOH)](Tp4Br)}·(C6H14)0.5 adduct is of particular interest as each 4-carboxylic
unit of 4-(diphenylphosphane)benzoic acid co-ligand in the monomer, interacts via hydrogen bonding
(O1–O2A = 2.62
) to each other to form a dimeric species assembled through formation of a cyclic
motif (Fig. 27) characteristic for aromatic carboxylic acids.305 More interesting is that the
supramolecular assemblies of hydrogen-bonded carboxylic acid dimers are mediated by an
intermolecular dihydrogen interaction (B–H H–C) as shown in Fig. 28. This diagram clearly shows
the head-to-tail alignment of 1·(C6H14)0.5 where the closest intermolecular contact occurs through a
rare hydrogen bond, which happens between the hydridic borane B–H terminus and the alkenic C–H
group of the pyrazole molecule (2.38( 2)
), where the estimated standard uncertainty (e.s.u.) was
evaluated from the e.s.u.'s of the parent atoms B and C. The positions of H atoms were idealized (B–H
and C–H = 0.96
2.65
) and not located in the Fourier map, nevertheless, the distance 2.38
is shorter than
, the sum of the van der Waals radius,306 showing an interaction.
81
Fig. 27. Formation of a chain based on the two O–H O hydrogen bonds (cyclic motif) of {Cu[PPh2(4C6H4COOH)](Tp4Br)}·(C6H14)0.5.
Fig. 28. Supramolecular assemblies of hydrogen-bonded carboxylic acid dimers mediated by a intermolecular dihydrogen
interaction (B-H…H-C) of {Cu[PPh2(4-C6H4COOH)](Tp4Br)}.(C6H14)0.5.
2.3. Antioxidant activity
The chemiluminescence technique was employed to evaluate the superoxide scavenging activity of the
new copper(I) complexes 1, 3, 4 and of Cu2(aspirinate)4 complex307 by using lucigenin as a
chemiluminogenic probe. The compound 2 was not analyzed because of its poor solubility.
This assay is based on the principle that the superoxide anion, generated by the xanthine/xanthine
oxidase system, reacts with lucigenin oxidizing it to N-methylacridone. N-methylacridone is in an
excited state and on returning to the fundamental state, emits light. The level of chemiluminescence
82
indicates the presence of superoxide in the medium under study; in other words, chemiluminescence
can be used for evaluating free superoxide radicals, i.e., those that have not reacted with antioxidants.
Fig. 29 shows the changes in lucigenin CL when superoxide dismutase (SOD), different copper(I)
complexes, and TEMPO were added to the reaction mixture consisting of the superoxide radicalgenerating system xanthine/xanthine oxidase and lucigenin. SOD causes a significant inhibition in CL
values; a complete inhibition was obtained using less than 0.01 µM SOD. All the copper(I) complexes
were able to scavenge the superoxide radical; the 50% of CL signal inhibition was obtained by adding
6.2, 0.55 and 2.3 µM solutions for complexes 1, 3 and 4, respectively. The Cu2(aspirinate)4 drug
reduces the CL signal similarly to copper(I) compounds. Obviously, the effect of these compounds is
less pronounced with respect to superoxide dismutase (50% of CL signal inhibition is obtained by
adding 0.005 µM of enzyme). However the superoxide scavenging activity of our complexes is more
marked with respect to the well-known nitroxide radical TEMPO and comparable to the copper(II)
drug. This activity has been reported by us for other copper(I) complexes.252
Fig. 29. Inhibition (%) of lucigenin-amplified chemiluminescence of the xanthine/xanthine oxidase system in the presence
of superoxide dismutase, TEMPO, Cu2(aspirinate)4 and copper(I) complexes. Chemiluminescence was measured in the
presence of 0.9 U ml–1 xanthine oxidase and 150 µM lucigenin; the reaction was initiated by injecting xanthine at a final
concentration of 50 mM in Tris 50 mM pH 7.4 buffer. Inhibition values refer to peak heights. (×) TEMPO; ( ) 1; ( ) 4;
( ) 3; ( ) Cu2(aspirinate)4, ( ) SOD.
83
The extent of DNA strand breakage induced by incubating rat trachea epithelial cells with GSNOMEE, Angeli's salt and SIN-1, and the level of protection conferred by the presence of copper(I)
complexes, was quantified using the Comet assay. Cells with increased DNA damage display an
increased migration of genetic material in the direction of electrophoresis. DNA damage is quantified
by measuring the displacement of the genetic material between the cell nucleus (Comet head ) and the
resulting tail . The parameters used as an index of DNA damage are tail length, tail intensity and tail
moment; the latter being one of the best indices of induced DNA damage among the various
parameters, calculated by computerised image analysis. It considers both the length of DNA migration
in the Comet tail (tail length) and the percentage of nuclear material migrated out from the Comet head
in the Comet tail (tail intensity), therefore this was the parameter evaluated in this work.
Fig. 30 and Figs. B–C show the DNA damage in rat epithelial cells expressed as tail moment of the
different samples incubated for 20 min at 37 °C in the presence or absence of Angeli's salt (Fig. 30),
GSNO-MEE (Fig. B), and SIN-1 (Fig. C) and in the presence or absence of two concentrations (5 and
10 µM) of complex 1 and Cu2(aspirinate)4. The values of tail moment increased in all the samples
incubated with RNOS donors indicating DNA impairment. Complex 1 reduced the extent of DNA
damage caused by RNOS donors as can be seen by the decrease in tail moment values (Fig. 30 and Fig.
31–32). The copper(II) complex is able to protect from the DNA damage induced by GSNO-MEE
donor at both concentrations tested but is less efficient than complex 1 when it is used in the presence
of SIN-1 and AS. A similar protective effect against DNA damage induced by the same RNOS donors
on the same cells was recently reported by us for different nitroxide stable radicals including TEMPO.
For the other copper(I) complexes 3 and 4 although they presented the highest superoxide scavenging
activity (Fig. 29) they were less efficient than complex 1 and their ability to reduce tail moment values
depended on the type of RNOS donor used. Complex 4 reduced the extent of DNA damage only when
this is caused by the RNOS donor SIN-1, whilst the protective effect of complex 3 is present only when
we used GSNO-MEE (data not shown).
84
Tail Moment (arbitrary unit)
3
2.5
2
1.5
1
*
**
0.5
**
**
pl
ex
ex
co
m
co
m
pl
+1
0u
M
+5
uM
AS
AS
+1
0u
M
+5
uM
AS
AS
1
1
at
e)
4]
u(
I I)
2(
as
pi
rin
[C
u(
II)
2(
as
pi
rin
at
e)
4]
[C
AS
co
nt
ro
l
0
Fig. 30 Effects of copper(I) complex 1 and of Cu2(aspirinate)4 complex on DNA of rat trachea epithelial cells incubated in
the presence of Angeli's salt (Na2N2O3). The tail moment parameter is reported using the Comet assay after 20 min
incubation at 37 °C in the presence or absence of 200 µM of the NO –-donor (Angeli's salt = AS) and in the presence or
absence of 5 and 10 µM complexes. Data, reported as mean values ± error standard, refer to at least three individual
1.2
1
0.8
0.6
0.4
**
**
0.2
**
***
1
co
m
pl
ex
pl
ex
E+
10
uM
co
m
E+
5u
M
SN
O
-M
E
O
-M
E
SN
G
G
SN
G
O
-M
E
1
na
te
)4
]
4]
E+
10
uM
[C
E+
5u
M
[C
O
-M
E
SN
G
u(
II)
2(
as
pi
ri
O
-M
E
SN
G
u(
II)
2(
as
pi
ri n
at
e)
E
0
co
nt
ro
l
Tail Moment (arbitrary unit)
experiments, three slides experiment–1. *p < 0.05; **p < 0.01.
Fig. 31 Effects of copper(I) complex 1 and of Cu2(aspirinate)4 complex on DNA of rat trachea epithelial cells incubated in
the presence of GSNO-MEE. The ‘tail moment’ parameter is reported using the comet assay after 20 min incubation at
37°C in the presence or absence of 150 M NO-donor (GSNO-MEE) and in the presence or absence of 5 and 10 M
complexes. Data, reported as mean values ± error standard, refer to at least three individual experiments, three
slides/experiment. ** p < 0.01; *** p < 0.001.
85
1.2
1
0.8
0.6
*
0.4
*
**
0.2
u(
II)
2(
as
SI
pi
N
rin
1+
at
10
e)
4]
uM
[C
u(
II)
2(
as
pi
rin
at
e)
4]
SI
N
1+
5u
M
co
m
pl
ex
1
SI
N
1+
10
uM
co
m
pl
ex
1
SI
N
1+
5u
M
[C
SI
N
1
0
co
nt
ro
l
Tail Moment (arbitrary unit)
1.4
Fig. 32 Effects of copper(I) complex 1 and of Cu2(aspirinate)4 complex on DNA of rat trachea epithelial cells incubated in
the presence of SIN-1. The ‘tail moment’ parameter is reported using the comet assay after 20 min incubation at 37°C in the
presence or absence of 1 mM SIN-1 and in the presence or absence of 5 and 10 M complexes. Data, reported as mean
values ± error standard, refer to at least three individual experiments, three slides/experiment. * p < 0.05; ** p < 0.01.
In conclusion, the results presented here show that the new copper(I) complex {Cu[PPh 2(4C6H4COOH)](Tp4Br)}, 1, is efficient at inhibiting the DNA damage induced by different RNOS donors.
Its antioxidant activity is similar or better than that of the copper(II) drug Cu 2(aspirinate)4, already
known for its anti-inflammatory properties. The data are promising for the potential use of copper(I)
complexes as therapeutic agents.
86
Chapter 4
A New Ester Substituted Heteroscorpionate Ligand
Since the first report of Trofimenko,1 poly(pyrazolyl)borates and related ligands276 have been
extensively employed as anionic σ-donor ligands in a wide variety of metal complexes that have found
application
in
coordination,
organometallic,
and
bioinorganic
chemistry.7
Modified
poly(pyrazolyl)borates can be made by replacement of the boron bridging atom with carbon,182
silicon308, or phosphorus.309,310 Other important variations can be effected by replacing the pyrazolyl
with triazolyl,311 imidazolyl,159,312 and methimazolyl moieties143 or by changing the substituents on the
heterocyclic ring to yield sterically restricted ligands to control the size and shape of the metal binding
cavities.13 In this field some recent relevant contributions are related to the simple H-bond accepting
scorpionate ligands, derived from ester substituted pyrazoles, which simultaneously provide both steric
bulk and hydrogen bonding groups, which can be directed towards the center of a metal binding
cavity313 or able to function as a host for something other than a metal cation.314,315
To our knowledge, to date, no bis(pyrazolyl)borates containing an ester function have been prepared,
presumably due to difficulties in the synthesis of ligands having both BH2 and carboxylate groups.
However, a bis(pyrazolyl)borate containing two carboxylates could be of interest due to its potential as
an N2O2 donor, not imposing a tripodal coordination but shielding the metals from attack by chelating
and sterically hindered ligands and stabilizing low coordination numbers.
Since one goal of our research is the introduction of a hydrophilic moiety to obtain complexes that are
soluble and stable under physiological conditions in view of potential biological applications, the
dihydrobis(pyrazolyl)borate and the analogous bis(pyrazolyl)methane ligands, obtained from 3- or 5carboxyethyl substituted pyrazole rings, appeared suitable candidates.252,257,263,316 This communication,
as part of our initial investigations into the transition metal coordination chemistry of this new class of
multifunctional ligands, describes the synthesis and the characterization of the potassium dihydrobis(3carboxyethyl-5-methylpyrazolyl)borate salt, K[BpCOOET,Me], and of the related copper(I) phosphane
complex Cu(BpCOOET,Me)PPh3.
87
1. Experimental section
1.1. General procedures
All reagents were purchased from Aldrich and used as received. All reactions were carried out under an
atmosphere of dry oxygen-free dinitrogen, using standard Schlenk techniques. All solvents were dried,
degassed and distilled prior to use. Elemental analyses (C,H,N,S) were performed with a Fisons
Instruments 1108 CHNS-O Elemental analyser. IR spectra were recorded from 4000 to 100 cm-1 with a
Perkin-Elmer System 2000 FT-IR instrument. 1H, 13C and 31P NMR spectra were recorded on a VXR300 Varian spectrometer operating at room temperature (300 MHz for 1H, 75 MHz for 13C and 121.4
MHz for
31
P). Electrospray mass spectra were obtained in positive- or negative-ion mode on a Series
1100 MSD detector HP spectrometer, using a methanol mobile phase. The compounds were added to
the reagent grade methanol to give solutions of approximate concentration 0.1 mM. These solutions
were injected (1 l) into the spectrometer via a HPLC HP 1090 Series II fitted with an autosampler.
The pump delivered the solutions to the mass spectrometer source at a flow rate of 300 l min-1, and
nitrogen was employed both as a drying and nebulizing gas. Capillary voltages were typically 4000 V
and 3500 V for the positive- and negative-ion mode, respectively. Confirmation of all major species in
this ESIMS study was aided by comparison of the observed and predicted isotope distribution patterns,
the latter calculated using the IsoPro computer program.
1.2. Synthesis of 3-methyl-5-carboxyethylpyrazole
Ethyl 2,4-diketopentanoate (25.0 g, 0.16 mol) was dissolved in 400 mL of ethanol and treated with an
excess (10.4 g, 0.21 mol) of hydrazine hydrate. The reaction mixture was heated at gentle reflux for 6
hours. The mixture was allowed to cool to r.t. and the solvent was removed by rotary evaporation to
obtain a pale yellow oil. The mixture was extracted with CHCl3, dried over Na2SO4 and volatiles
removed under reduced pressure. The crude product was recrystallized from diethyl ether. Yield 84%;
m.p. 80-82°C. 1H NMR (CDCl3) δ 1.30 (t, 3H, CH3), 2.39 (s, 3H, CH3), 4.32 (q, 2H, -OCH2-), 6.57 (s,
1H, CH).
13
C NMR (CDCl3, 293 K):  11.45 (CH3), 14.26 (CH3), 61.18 (CH2), 107.52 (CH), 141.11
(CCH3), 143.71 (CCOOEt), 160.81 (COOEt). IR (nujol mull, cm-1): 3161w, 3129w (CH), 1524m (C=C
+ C=N). Calcd for C7H10N2O2: C, 54.54; H, 6.54; N, 18.17 %. Found: C, 54.50; H, 6.57; N, 18.20 %.
88
1.3. Synthesis of K[BpCOOET,Me] (1)
KBH4 (0.90 g, 16.7 mmol) and 3-methyl-5-carboxyethylpyrazole (6.60 g, 42.8 mmol) were mixed in
kerosene (15 ml), and the mixture was heated slowly under N2 until reflux began. The refluxing was
continued for 6 h, and the volatiles were removed under reduced pressure. The resulting oily residue
was dissolved with a minimum amount of acetone and cooled at 0°C; diethyl ether was added to obtain
a colorless and microcrystalline solid in 85% yield. Mp: 206-208 °C. 1H NMR (acetone, 293K):  1.29
(t, 6H, CH3), 2.24 (s, 6H, CH3), 4.24 (q, 4H, CH2), 6.26 (s, 2H, CH). 1H NMR (CDCl3, 293K):  1.23
(t, 6H, CH3), 2.34 (s, 6H, CH3), 4.11 (q, 4H, CH2), 6.32 (s, 2H, CH).
13
C NMR (CDCl3, 293 K): 
12.91 (CH3), 14.43 (CH3), 60.61 (CH2), 106.69 (CH), 142.11 (CCH3), 144.01 (CCOOEt), 164.31
(COOEt). IR (nujol mull, cm-1): 3190w (CH), 2450m, 2424m, 2387m, 2366m (BH), 1716s (C=O),
1533m (C=C + C=N), 535w, 427m, 344w, 330m. ESIMS (major positive-ions, CH3OH), m/z (%): 321
(40) [(BpCOOET,Me) + 2H+]+, 343 (100) [(BpCOOET,Me) + H+ + Na+]+. ESIMS (major negative-ions,
CH3OH), m/z (%): 319 (100) [BpCOOET,Me]-. Calcd for C14H20BKN4O4: C, 46.94; H, 5.63; N, 15.64 %.
Found: C, 46.80; H, 5.55; N, 14.78 %.
1.4. Synthesis of Cu(PPh3)(BpCOOET,Me) (2)
To a CH3OH/CH3CN (1/1) solution (50 ml) of CuCl (0.099 g, 1.0 mmol) and PPh3 (0.262 g, 1.0 mmol),
KBpCOOET,Me (0.358 g, 1.0 mmol) was added at room temperature. After the addition, the solution was
stirred for 5 h and the solvent subsequently removed with a rotary evaporator. CHCl 3 (50 ml) was
added; the suspension was filtered and concentrated under reduced pressure. A colorless precipitate
was formed, which was filtered off and washed with diethyl ether. Re-crystallization from CH2Cl2petroleum ether gave complex 2 as a microcrystalline solid in 75% yield. Mp: 138-143 °C. 1H NMR
(CDCl3, 293K):  0.96 (t, 6H, CH3), 2.37 (s, 6H, CH3), 4.78 (q, 4H, CH2), 6.43 (s, 2H, CH), 7.30-7.55
(m, 15H, CH).
13
C NMR (CDCl3, 293 K):  12.85 (CH3), 14.49 (CH3), 60.33 (CH2), 107.70 (CH),
128.59 (CH), 128.78 (CH), 129.94 (CH), 133.19 (Cipso), 134.06 (CH), 134.37 (CH), 141.87 (CCH3),
144.54 (CCOOEt), 162 (br, COOEt). 31P{1H} NMR (CDCl3, 293 K):  2.62 (s). IR (nujol mull, cm-1):
3139w (CH), 2470m, 2370w, 2322w (BH), 1710sbr, 1531m (C=C + C=N), 529s, 504s, 498s, 459w,
445m, 426m, 397m, 344m. ESIMS (major positive-ions, CH3CN), m/z (%): 343 (60) [(BpCOOET,Me) +
Na+ + H+]+, 366 (20) [(BpCOOET,Me) + 2Na+]+, 588 (40) [Cu(PPh3)2]+, 646 (100) [Cu(PPh3)(BpCOOET,Me)
+ H+]+, 668 (20) [Cu(PPh3)(BpCOOET,Me) + Na+]+, 726 (40) [Cu2(PPh3)(BpCOOET,Me)(H2O)]+, 971 (10)
[Cu2(PPh3)2(BpCOOET,Me)]+. ESIMS (major negative-ions, CH3CN), m/z (%): 319 (100) [BpCOOET,Me]-,
89
408 (30) [{Cu(BpCOOET,Me)(OH)}2(H2O)]2-, 498 (20) [Cu2(BpCOOET,Me)(OH)2(H2O)]-. Anal. Calcd for
C32H35BCuN4O4P; C, 59.59; H; 5.47; N, 8.69. Found: C, 59.70; H; 4.52; N, 8.42 %.
2. Results and discussion
The potassium salt of the bis(pyrazolyl)borate ligand 1 is readily prepared in kerosene using KBH4 and
3-methyl-5-carboxyethylpyrazole. This product has been isolated in high yield and characterized by 1H,
13
C NMR and FT-IR spectroscopy, Electrospray ionization mass spectroscopy (ESI-MS) and elemental
analysis. Reaction between K[BpCOOET,Me], copper chloride and PPh3 in acetonitrile and methanol
solution at room temperature, readily gives complex 2 in good yields (Scheme 23).
Scheme 23
The same compound was obtained even when a large excess of phosphane ligand was employed, the
stoichiometry of this kind of complex being essentially independent of the ligand-to-metal ratio
employed. The colorless compound 2 is soluble in H2O/EtOH mixture, acetonitrile, acetone and
chlorinated solvents and air stable, even in solution. In the infrared spectrum, the B–H stretches appear
at 2322–2470 cm−1. Upon coordination, these bands are slightly shifted with respect to the same
absorptions observed for the free ligands. The strong absorption at 1710 cm−1, due to the carboxylate
asymmetric stretch, is slightly shifted to smaller wave numbers with respect to the same absorptions
observed for the free ligand (1716 cm−1), consistent with a weak interaction in the solid state between
the carboxylate group and the copper metal center, as recently observed for analogous compounds. 317
The room temperature 31P NMR spectra of 2 in chloroform solution exhibit a slightly broadened signal
centered at 2.62 ppm, compared with the sharp singlet at −4.8 ppm exhibited by uncoordinated
triphenylphosphane; no signal due to any oxidized form was detected.
90
Electrospray ionization mass spectroscopy was used to probe the existence of aggregates of
triphenylphosphane and the scorpionate ligand 1 with copper(I) in solution. Both positive-ion and
negative-ion spectra of the ligand 1 and the related derivative 2 dissolved in methanol or acetonitrile,
respectively, were recorded at low fragmentor voltage; in these conditions the dissociation is minimal
and a high proportion of the analyte is transported to the mass spectrometer as the intact molecular
species. The positive-ion spectrum of the ligand 1 in methanol is dominated by a fragment at m/z 343
(100%) attributable to the aggregation of a proton and a sodium ion to the ligand. The ligand ion (m/z
319, 100%) dominates the negative-ion ESI-MS spectrum of the free ligand and of compound 2. The
positive-ion
spectrum
of
compound
2
is
dominated
by
the
protonated
species
[Cu(PPh3)(BpCOOET,Me) + H+]+, (m/z 646, 100%). Some further peaks due to the aggregates of copper(I)
with scorpionate and phosphane ligands have also been detected and identified by the characteristic
isotope distribution patterns.
A ‘low’-temperature single crystal X-ray structure determination confirms the formulation of the
copper(I) complex to be mononuclear Cu(BpCOOET,Me)PPh3 , one molecule, devoid of crystallographic
symmetry, comprising the asymmetric unit. The coordination environment of the copper is essentially
trigonal planar PCuN2 (Fig. 33) with longer contacts to either oxygen of the two ester groups.
Cu(BpCOOET,Me)PPh3 exhibits a short Cu B distance (3.023(3) Å), which suggests the existence of
some B–H Cu interaction, the unsaturated trigonal coordination environment perhaps partially
compensated by placing the B–H bond and both carboxylate groups in a suitable position for donor
interaction with the empty metal bonded orbital. The possibility of B–H Cu interaction seems to be
supported also by B–H stretching vibrations, which exhibit a different pattern with respect to that found
for bis(pyrazolyl)borate copper complexes and also for KBpCOOET,Me.
91
Fig. 33.. A single molecule of Cu(BpCOOET,Me)PPh3 (2) showing 50% probability amplitude displacement ellipsoids for the
non-hydrogen atoms, hydrogen atoms having arbitrary radii of 0.1 Å. Cu–P(1) 2.1718(6), Cu–N(11) 2.026(2), Cu–N(21)
2.007(2), Cu–O(151) 3.288(2), Cu–O(252) 3.115(2) Å. N(11)–Cu–N(21) 96.77(7), P(1)–Cu–N(11) 124.86(6), P(1)–Cu–
N(21) 137.42(5) (∑ 359.0°).
In
conclusion, a new potassium
dihydrobis(3-carboxyethyl-5-methylpyrazolyl)borate ligand,
designated KBpCOOET,Me, has been synthesized and fully spectroscopically and analytically
characterized. A new copper(I) derivative, Cu(BpCOOET,Me)PPh3 , soluble in methanol/water solution, a
feature interesting in view of biological applications, has been obtained from the reaction of
KBpCOOET,Me with CuCl and PPh3 and has been structurally characterized.
92
Chapter 5
The First Nitro-Substituted Heteroscorpionate
Ligand
In literature very little works are present as regards about poly(pyrazolyl)borate systems bearing
electron withdrawing substituents.79,313,318-320 In 1995, Dias65 and Venanzi66,123 reported the synthesis of
ligands containing highly electron withdrawing trifluoromethyl substituents, and over the past few
years, Dias and others321 reported the synthesis and/or uses of several poly(pyrazolyl)borates
containing fluoroalkyl substituents. The electron withdrawing substituents in polyfluorinated ligands
commonly improve the volatility, oxidation resistance, thermal stability, and solubility of metal
complexes. Considering this success, me and my research group, decided to investigate a new class of
electron withdrawing substituted poly(azolyl)borate ligands, derived from nitro-substituted heterocyclic
rings. In this session, I report the synthesis and characterization of an unprecedent heteroscorpionate
ligand, dihydridobis(3-nitro-1,2,4-triazolyl)borate, [H2B(tzNO2)2]-. To my knowledge, to date, no
poly(azolyl)borates containing a -NO2 function have been prepared, presumably due to difficulties in
the synthesis of ligands having both a hydride and a nitro group. However, a bis(triazolyl)borate
containing a -NO2 substituent could be of interest due to its high coordinative flexibility from
2
- to
4
-
N2O2 coordination ability.
1. Experimental
1.1. General procedures
All reagents were purchased from Aldrich and used as received. All reactions were carried out under an
atmosphere of dry oxygen-free dinitrogen, using standard Schlenk techniques. All solvents were dried,
degassed and distilled prior to use. Elemental analyses (C,H,N,S) were performed with a Fisons
Instruments 1108 CHNS-O Elemental analyser. IR spectra were recorded from 4000 to 100 cm-1 with
a Perkin-Elmer System 2000 FT-IR instrument. 1H,
13
C and
113
Cd NMR spectra were recorded on a
93
VXR-300 Varian spectrometer operating at room temperature (300 MHz for 1H, 75 MHz for
13
C and
66.55 MHz for 113Cd). Electrospray mass spectra were obtained in positive- or negative-ion mode on a
Series 1100 MSD detector HP spectrometer, using a methanol mobile phase. The compounds were
added to the reagent grade methanol to give solutions of approximate concentration 0.1 mM. These
solutions were injected (1 μl) into the spectrometer via a HPLC HP 1090 Series II fitted with an
autosampler. The pump delivered the solutions to the mass spectrometer source at a flow rate of 300 μl
min-1, and nitrogen was employed both as a drying and nebulizing gas. Capillary voltages were
typically 4000 V and 3500 V for the positive- and negative ion mode, respectively. Confirmation of all
major species in this ESIMS study was aided by comparison of the observed and predicted isotope
distribution patterns, the latter calculated using the IsoPro computer program.
1.2. Synthesis of {Zn[H2B(tzNO2)2]Cl(H2O)2} (2)
To a solution of ZnCl2 (0.136 g, 1 mmol) in 50 mL of acetone was added K[H2B(tzNO2)2] (0.278 g, 1
mmol) and the mixture was kept at room temperature and stirred for 4 h. The salt was filtered off and
the solvent removed by a rotary evaporator. Re-crystallization with acetone/diethyl ether gave complex
2 as a microcrystalline colorless solid. The same reaction conducted with a 2:1 ratio of ligand/ZnCl2
gave however the compound 2. Yield: 90%. Mp: 104°C dec. 1H NMR (CD3OD, 293 K): 2 δ 8.38 (s,
5C-H). 13C NMR (CD3OD, 293 K): 151.32 (s, 5-CH), 165.50 (s, 3-CNO2). IR (nujol, cm-1): 3414mbr
(H-OH); 3128w (CH); 2468m, 2439m (BH); 1621wbr (C=C + C=N); 1540s (νas(NO2)); 1303s
(νs(NO2)). ESIMS (CH3OH): (-) 113 (20) [tzNO2]-, 239 (100) [H2B(tzNO2)2]-. ESIMS (CH3OH): (+) 304
(40) [Zn{H2B(tzNO2)2}]+, 317 (100) [{H2B(tzNO2)2} + 2K]+, 454 (60) [ZnCl{H2B(tzNO2)2}(tzNO2) +
2H]+, 595 (30) [{H2B(tzNO2)2}2 + 3K]+. Anal. Calcd for C4H8BClN8O6Zn: C, 12.78; H, 2.15; N, 29.82.
Found: C, 12.60; H, 2.28; N, 30.32.
1.3. Synthesis of {Cd[H2B(tzNO2)2]Cl(H2O)2} (3)
To a solution of CdCl2 (0.183 g, 1 mmol) in 50 mL of acetone was added K[H2B(tzNO2)2] (0.278 g, 1
mmol) and the mixture was kept at room temperature and stirred for 4 h. The salt was filtered off and
the solvent removed by a rotary evaporator. Re-crystallization with acetone/diethyl ether gave
compound 3 as a microcrystalline colorless solid. The same reaction conducted with a 2:1 ratio of
ligand/CdCl2 gave however the compound 3. Yield: 95%. Mp: 210 dec.. 1H NMR (D2O, 293 K): δ 8.26
(s, 2H, 5C-H).
13
C NMR (CD3OD, 293 K): 152.41 (s, 5-CH), 165.9 (s, 3-CNO2).
113
Cd NMR (D2O,
293 K): δ 46.15 (s). IR (nujol, cm-1): 3375wbr (HO-H); 3128w (CH); 2468m, 2440m (BH); 1628wbr
94
(C=C + C=N); 1540s (νas(NO2)); 1302s (νs(NO2)). ESIMS (CH3OH): (-) 239 (100) [H2B(tzNO2)2]-.
ESIMS (CH3OH): (+) 317 (100) [{H2B(tzNO2)2} + 2K]+, 360 (50) [Cd2{H2B(tzNO2)2}2(H2O)]++, 445
(40) [CdCl{H2B(tzNO2)2}(H2O)2 + Na]+, 595 (30) [{H2B(tzNO2)2}2 + 3K]+. Anal. Calcd for
C4H8BCdClN8O6: C, 11.36; H, 1.91; N, 26.50. Found: C, 11.45; H, 1.74; N, 26.39.
2. Results and discussion
This new ligand represents the 3-nitro-substituted analogues of one of the most widely used
dihydridobis(1,2,4-triazolyl)borate255 and dihydridobis(1,2,3-benzotriazolyl)borate ligands.176
The potassium salt of [dihydridobis(3-nitro-1,2,4-triazolyl)borate], 1, has been synthesized by treating
KBH4 with 3-nitro-1,2,4-triazole in DMAC solvent. Compound 1 is an air- and moisture-stable
colorless solid; it is soluble inacetone, and in protic solvents as water, methanol, and ethanol. The
reaction of 1 with KH in THF solution results in the reduction of the nitro to ammine groups and
formation of an oligomer mixture of the composition [H2B(tzNH2)2]n species (n = 2-4) identified by
mass spectrometry, in which the dimeric triazabole, [H2B(tzNH2)2BH2], is the major species.322 From the
interaction of 1 equiv of 1 with 1 equiv of zinc(II) chloride or cadmium(II) chloride (see eqn. 1), in
acetone
at
room
temperature,
the
{Zn[H2B(tzNO2)2]Cl(H2O)2},
complexes
2,
and
{Cd[H2B(tzNO2)2]Cl(H2O)2}, 3, have been obtained in high yield:
NO2
K[H2B(tz
)2] + MCl2
NO2
M[H2B(tz
)2]Cl(H2O)2 + KCl
(1)
2, M = Zn(II)
3, M = Cd(II)
The same compounds have been obtained even when an excess of ligand 1 was employed. Both the
colorless compounds 2 and 3 are soluble in methanol and in water solution and air stable even as in
solutions. This property offers the possibility of applications in bioinorganic study.323
Ligand 1 and complexes 2 and 3 have been isolated in high yield and characterized by 1H and
13
C
NMR and FT-IR spectroscopy, electrospray ionization mass spectroscopy (ESI-MS), and elemental
analysis.
In the infrared spectrum of 1, the B-H stretching appears at 2469 and 2440 cm-1, and the asymmetric
and symmetric stretching of -NO2 group appears at 1538 and 1304 cm-1. The asymmetric and
symmetric stretchings of the -NO2 group appear at 1520 and 1310 cm-1 in the neutral nitrotriazole.
95
These bands are only slightly shifted upon coordination, consistent with a weak interaction in the solid
state between the nitro group and the zinc or cadmium metal center. The
13
C chemical shifts of 5-CH
and 3-CNO2 carbons (in CD3OD solution) at 151.28 and 165.37, respectively, are close to those of the
starting triazole ( 146.20 and 163.20 in DMSO-d6).
Electrospray ionization mass spectroscopy was used to probe the existence of aggregates of the
scorpionate ligand 1 with zinc(II) and cadmium(II) in solution. Both positive-ion and negative-ion
spectra of ligand 1 and the related derivatives 2 and 3, dissolved in methanol, were recorded at low
fragmentor voltage; in these conditions the dissociation is minimal, and a high proportion of the analyte
is transported to the mass spectrometer as the intact molecular species. The positive-ion spectrum of
ligand 1 and compounds 2 and 3 in methanol is dominated by a fragment at m/z 317 (100%)
attributable to the aggregation of two potassium ions to the ligand.
The ligand ion (m/z 239, 100%) dominates the negative-ion ESI-MS spectra of 1-3. In the positive-ion
spectrum of compounds 2 and 3, some further peaks due to the aggregates of Zn(II) and Cd(II) with
scorpionate ligand, chloride, and water have also been detected and identified by the characteristic
isotope distribution patterns. For the cadmium derivative 3, the 113Cd NMR spectrum in water solution
has been obtained and a unique absorption has been detected which falls at 46.15 ppm, in the typical
region of five- or six-coordinate cadmium species.324
Fig. 34. Structure of the anion, bonded to the potassium ions.
96
Table 4 Selected bond distances (Å) and angles (deg) for [H2B(tzNO2)2]- anion
Atom
Parameters
Distances/
N(4)-O(1)
N(4)-O(2)
N(8)-O(3)
N(8)-O(4)
B-N(1)
B-N(5)
N(1)-C(1)
N(1)-N(2)
N(2)-C(2)
C(2)-N(3)
C(1)-N(3)
C(2)-N(4)
N(5)-N(6)
N(5)-C(3)
C(3)-N(7)
C(4)-N(6)
C(4)-N(7)
C(4)-N(8)
1.217(3)
1.215(3)
1.224(3)
1.226(3)
1.567(4)
1.559(3)
1.330(4)
1.357(3)
1.319(3)
1.325(3)
1.331(4)
1.449(5)
1.356(3)
1.339(3)
1.325(3)
1.313(3)
1.339(3)
1.445(3)
Angles/°
N(1)-B-N(5)
O(1)-N(4)-O(2)
O(1)-N(4)-C(2)
O(2)-N(4)-C(2)
O(3)-N(8)-O(4)
O(3)-N(8)-C(4)
O(4)-N(8)-C(4)
109.1(5)
123.5(2)
118.3(2)
118.1(2)
124.7(2)
117.9(2)
117.4(2)
The crystal and molecular structure of [H2B(tzNO2)2]K has been determined by X-ray analysis. Fig. 34
shows an ORTEP view of the anion coordinated to the potassium ions. The resulting coordination
polyhedron is a rather irregular tricapped trigonal prism, distorted for the insertion of the agostic BH···K bond (shown as dotted line but not considered in the coordination polyhedron) (Fig. 35).
97
Fig. 35. Potassium coordination polyhedron. Selected bond lengths (Å): K-O(2) 2.970(3), K-N(2) 2.912(2), K-N(6)
2.979(2), K-O(3) 3.162(3), K-O(1)I 3.100(2), K-O(2)I 3.049(3), K-O(1)II 2.873(3), K-N(3)II 2.882(2), K-N(7)III 2.923(2), KH(2)IV 3.03(3).
Similar agostic interactions have been reported for related tetrazolyl derivative [H2B(CHN4)2]K. The
two nitro functionalities of the ligand are coplanar to the respective triazolyl ring, while the latter is
inclined 64.4(1)
with respect to the other.
98
Chapter 6
New Copper(I) phosphane complexes of
dihydrobis(3-nitro-1,2,4-triazolyl)borate ligand
showing cytotoxic activity
It is known that copper is an essential trace metal for living organisms.325 This metal plays a crucial
role in different enzymes that catalyze oxidation/reduction reactions correlated with the antioxidant
system of the organism concerned,326 reversible dioxygen binding,327 two-electron reduction to
peroxide coupled to oxidation of substrates,328 activation for hydroxylation and the four-electron
reduction to water coupled to substrate oxidation329 or proton pumping.330 It has been reported that
certain copper-complexes catalyze radical formation while others seem to have antioxidant efficacy:331
the different behavior depends upon the chemical environment and the nature of the chelating
agent.252,332,333 Some mixed chelate copper-based drugs have exhibited greater antineoplastic potency
than cisplatin in in vitro and in vivo studies of a variety of tumor cell lines.334 These copper-based
drugs also show superoxide dismutase-like activity335 and a low potency to induce genomic instability
through intrachromosomal recombination.336 In addition, copper(II) complexes of chelate
phenanthroline and bipyridine ligands show high antineoplastic activity; these species affected several
different mitochondrial sites, bringing about inhibition of respiration and ATP synthesis, which could
compromise energy-dependent processes such as cellular duplication.337
Phosphane and phosphanoethane ligands are broadly used in synthesis of gold, silver and copper
complexes.338,339 In particular, copper(I) phosphane complexes are also of interest because of their
tumoricidal properties.340,341 Progress in the application of the complexes requires understanding of the
factors governing their structural and stoichiometric preferences.342
Poly(pyrazolyl)borates1 and related scorpionate ligands have been extensively employed as anionic σdonor ligands in a wide variety of metal complexes, and they have found wide application in
coordination, organometallic, and bioinorganic chemistry.276 In particular poly(pyrazolyl)borate copper
99
derivatives, synthesized in order to model various properties of copper-containing natural products,
have been discussed in a review devoted to the structure and function of copper proteins.277 Very little
has
been
done
on
poly(pyrazolyl)borate
systems
bearing
electron
withdrawing
substituents.65,66,79,123,313,318-320 The electron withdrawing substituents in polyfluorinated ligands
commonly improve oxidation resistance, thermal stability, and solubility of metal complexes. 321
Considering the variety of effects induced by these substituents, I decided to investigate a new class of
electron withdrawing substituted poly(azolyl)borate ligands, derived from nitro-substituted heterocyclic
rings. In Chapter 4 I have reported the synthesis and characterization of the first nitro-substituted
heteroscorpionate ligand, dihydridobis(3-nitro-1,2,4-triazolyl)borate [H2B(tzNO2)2]− (Fig. 36).343 This
new ligand represents the 3-nitro-substituted analog of the widely used dihydridobis(1,2,4triazolyl)borate and dihydridobis(1,2,3-benzotriazolyl)borate ligands.255 Triazole-based ligands are
electron-withdrawing systems compared to their pyrazole-based counterparts. The –NO2 substituted
scorpionate ligands could be of interest due to its high coordinative flexibility from κ2-N2 to κ4-N2O2
coordination ability.
H
H
B
N
N
N
N
N
N
O2N
NO2
[H2B(tzNO2)2]Fig. 36.. Structure of the scorpionate ligand employed in this work.
This paper, as part of my initial investigations into the scorpionate copper(I) coordination chemistry
describes the synthesis and the spectroscopic and analytic characterization of new copper(I) complexes
containing phosphane co-ligands.
The cytotoxic activity of selected hydrophilic copper(I) complexes has also been evaluated against a
panel of human tumor cell lines. For comparison purpose, cisplatin, which is the most widely used
metal-based antitumor drug,344 was tested under the same experimental conditions.
100
1. Materials and methods
1.1. General procedures
All syntheses and handling were carried out under an atmosphere of dry oxygen–free dinitrogen, using
standard Schlenk techniques or a glove box. All solvents were dried, degassed and distilled prior to use.
Elemental analyses (C,H,N,S) were performed in house with a Fisons Instruments 1108 CHNS-O
Elemental Analyser. Melting points were taken on an SMP3 Stuart Scientific Instrument. IR spectra
were recorded from 4000 to 100cm−1 with a Perkin–Elmer System 2000 FT-IR instrument. IR
annotations used: m = medium, mbr = medium broad, s = strong, sbr = strong broad, sh = shoulder, w =
weak, wbr=weak broad. 1H and
31
P NMR spectra were recorded on a VXR-300 Varian spectrometer
(300 MHz for 1H, and 121.4 MHz for 31P). NMR annotations used: s = singlet, sbr = broad singlet, m =
multiplet.
1.2. Experimental
All reagents were purchased from Aldrich and used without further purification. The ligand potassium
dihydrobis(3-nitro-1,2,4-triazol-1-yl)borate K[H2B(tzNO2)2] was synthesized in accordance with the
literature method.343 Compounds 1–5 were prepared using an identical procedure below detailed for 1.
1.3. Synthesis of [H2B (tzNO2)2]Cu[P(m-tolyl)3]2 (1)
To a methanol/acetonitrile (1:2) solution (50 mL) of CuCl (0.099 g, 1.0 mmol) and tris(mtolyl)phosphane (0.608 g, 2.0 mmol), K[H2B(tzNO2)2] was added (0.278 g, 1.0 mmol) at room
temperature. After addition, the reaction mixture was stirred for 5 h, and the solvent was removed
under vacuum. The resulting white solid was treated with chloroform (50 mL) and the salt removed by
filtration. The filtrate was concentrated under vacuum and a white solid was filtered off, washed with
diethyl ether and re-crystallized from CHCl3/n-exane (1:3) to give complex 1 in 62% yield; m.p. 68°C
dec. 1H NMR (CDCl3, 293 K): δ 2.17 (s, 18 H, CH3), 7.01–7.17 (m, 24 H, CH), 8.05 (s, 2 H, 5-CH). 31P
NMR (CDCl3, 293 K): δ 0.10 (sbr).
(CH), 2431sbr (BH), 1561m (C
31
P NMR (CDCl3, 223 K): δ 0.78 (s). IR (nujol, cm−1): 3130m
C+C
N), 1521m (νasym N–O), 1342m (νsym N–O), 551sbr, 531sh,
456sbr (R3P), 367w, 356w (Cu–N). Anal. Calcd for C46H46BCuN8O4P2: C, 60.63; H; 5.09; N, 12.30.
Found: C, 60.49; H, 5.18; N, 12.38%.
101
1.4. Synthesis of [H2B (tzNO2)2]Cu[P(p-tolyl)3]2 (2)
72% yield; m.p. 115–116 C. 1H NMR (CDCl3, 293 K): δ 2.29 (s, 18H, CH3), 6.97–7.07 (m, 24 H, CH),
8.03 (s, 2 H, 5-CH). 31P NMR (CDCl3, 293 K): δ −0.84 (s). 31P NMR (CDCl3, 223 K): δ −0.87 (s). IR
(nujol, cm−1): 3116m (CH), 2419m (BH), 1596m (C
C+C
N), 1537m (νasym N–O), 1334m (νsym
N–O), 520sbr, 511sbr, 499mbr, 437w (R3P), 353wbr (Cu–N). Anal. Calcd for C46H46BCuN8O4P2: C,
60.63; H; 5.09; N, 12.30. Found: C, 60.78; H, 5.19; N, 12.13%.
1.5. Synthesis of [H2B(tzNO2)2]Cu[P(C6H5)2(p-C6H4COOH)]2 (3)
91% yield; m.p. 130–131 C. 1H NMR (CDCl3, 293 K): δ 7.21–7.74 (m, 28H, CH), 8.22 (s, 2 H, 5-CH).
P NMR (CDCl3, 293 K): δ −0.98 (sbr). 31P NMR (CDCl3, 223 K): δ 0.66 (s). IR (nujol, cm−1): 3086m
31
(CH), 2426mbr (BH), 1693m (C
O), 1594m (C
C+C
N), 1537m (νasym N–O), 1334m (νsym N–
O), 533mbr, 508mbr, 440m (R3P), 370w (Cu–N). Anal. Calcd for C42H34BCuN8O8P2: C, 55.13; H;
3.75; N, 12.25. Found: C, 54.90; H, 3.68; N, 12.17%.
1.6. Synthesis of [H2B (tzNO2)2]Cu[P(CH2C6H5)3]2 (4)
76% yield; m.p. 57 C dec. 1H NMR (DMSO, 293K): δ 2.92 (s, 12 H, CH2), 7.00–7.30 (m, 30 H, CH),
8.09 (s, 2 H, 5-CH).
P NMR (CDCl3, 293 K): δ 1.20 (sbr).
31
31
P NMR (CDCl3, 223 K): δ −8.41 (s),
−3.05 (s), 6.09 (s), 45.07 (s). IR (nujol, cm−1): 3128w, 3082m (CH), 2424sbr (BH), 1599m (C
C+C
N), 1548m (νasym N–O), 1333m (νsym N–O), 578mbr, 556m, 478sbr (R3P), 353w, 306w (Cu–
N). Anal. Calcd for C46H46BCuN8O4P2: C, 60.63; H; 5.09; N, 12.30. Found: C, 60.45; H, 5.19; N,
12.11%.
1.7. Synthesis of [H2B (tzNO2)2]Cu[P(p-C6H4F)3]2 (5)
63% yield; m.p. 98–99 C. 1H NMR (CD3OD, 293K): δ 7.05–7.43 (m, 24 H, CH), 8.23 (s, 2 H, 5-CH).
P NMR (CDCl3, 293 K): δ −4.0 (br). 31P NMR (CDCl3, 223 K): δ −4.81 (s). IR (nujol, cm−1): 3065m
31
(CH), 2428sbr (BH), 1587m (C
C+C
N), 1538m (νasym N–O), 1341m (νsym N–O), 527sbr, 466m,
444m, 437m, 407w (R3P), 341w, 312w (Cu–N). Anal. Calcd for C40H28BCuF6N8O4 P2: C, 51.38; H;
3.02; N, 11.98. Found: C, 51.10; H, 3.20; N, 11.77%.
102
1.8. Synthesis of [H2B (tzNO2)2]Cu{(C6H5)2PCH2CH2P(C6H5)2} (6)
Complex 6 was prepared analogously to compound 1 but using equimolar amount of CuCl (0.099 g,
1.0 mmol) (C6H5)2PCH2CH2P(C6H5)2 (bis(diphenylphosphane)ethane; dppe) (0.398 g, 1.0 mmol), and
K[H2B(tzNO2)2] (0.278 g, 1.0 mmol). The product was obtained by re-crystallization from CHCl3/nexane (1:3), in 63% yield. M.p. 63–64 C. 1H NMR (CDCl3, 293 K): δ 2.44 (s, 4 H, CH2), 7.19–7.30 (m,
20 H, CH), 8.23 (s, 2 H, 5-CH). 31P NMR (CDCl3, 293 K): δ 7.00 (sbr). 31P NMR (CDCl3, 223 K): δ
7.58 (s). IR (nujol, cm−1): 3174w (CH), 2421mbr (BH), 1614m (C
C+C
N), 1537m (νasym N–O),
1336m (νsym N–O), 510mbr, 477mbr (R3P), 367w, 337w (Cu–N). Anal. Calcd for C30H28BCuN8O4P2:
C, 51.41; H; 4.03; N, 15.99. Found: C, 51.65; H, 4.20; N, 15.75%.
1.9. Synthesis of [H2B (tzNO2)2]Cu[SeP(C6H5)3] (7)
Complex 7 was prepared analogously to compound 1 by using CuCl (0.099 g, 1.0 mmol),
tri(phenyl)phosphane selenide (0.341 g, 1.0 mmol), and K[H2B(tzNO2)2] (0.278 g, 1.0 mmol). The
product was obtained by re-crystallization from CHCl3/n-exane (1:3), in 57% yield. M.p. 114 C dec. 1H
NMR (CDCl3, 293 K): δ 7.40–7.72 (m, 15 H, CH), 8.00 (s, 2 H, 5-CH). 31P NMR (CDCl3, 293 K): δ
30.50 (sbr). 31P NMR (CDCl3, 223 K): δ 31.84 (s). IR (nujol, cm−1): 3130w, 3055w (CH), 2440m (BH),
1586w (C
C+C
N), 1548m (νasym N–O), 1377m (νsym N–O), 549s, 513sbr, 455w (R3P), 346w
(Cu–N). Anal. Calcd for C22H19BCuN8O4PSe: C, 41.05; H, 2.97; N, 17.41. Found: C, 40.86; H, 3.10;
N, 17.55%.
1.10. Synthesis of [H2B (tzNO2)2]Cu[P(C6H11)3] (8)
Complex 8 was prepared analogously to compound 1 by using CuCl (0.099 g, 1.0 mmol),
tricyclohexylphosphane (0.280 g, 1.0 mmol), and K[H2B(tzNO2)2] (0.278 g, 1.0 mmol). The product was
obtained by re-crystallization from CHCl3/n-exane (1:3), in 65% yield. M.p. 60–63 C. 1H NMR
(DMSO, 293 K): δ 1.23–1.94 (m, 33 H, C6H11), 8.46 (s, 2 H, 5-CH).
31
P NMR (DMSO, 293 K): δ
29.10 (sbr). IR (nujol, cm−1): 3130w (CH), 2431mbr (BH), 1630w (C
C+C
N), 1548m (νasym N–
O), 1349w (νsym N–O), 566mbr, 548mbr, 534mbr, 495w (R3P), 308w (Cu–N). Anal. Calcd for
C22H37BCuN8O4P: C, 45.33; H, 6.40; N, 19.22. Found: C, 45.07; H, 6.19; N, 19.00%.
103
1.11. Experiments with human cells
Complexes [H2B(tzNO2)2]Cu[P(m-tolyl)3]2, 1, [H2B (tzNO2)2]Cu[P(C6H5)2(p-C6H4COOH)]2, 3, and [H2B
(tzNO2)2]Cu[P(p-C6H4F)3]2, 5, and the corresponding uncoordinated ligands were dissolved in purified
water just before the experiments; cisplatin, used for comparison purpose, was dissolved in dimethyl
sulphoxide (DMSO) and a calculated amount of drug solution was added to the growth medium
containing cells to a final solvent concentration of 0.5% which had no discernible effect on cell killing.
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) bromide and cisplatin were obtained from
Sigma Chemical Co., St. Louis, USA.
1.12. Cell cultures
A549 human lung carcinoma cell line was obtained from ATCC (RocKville, MD) along with
melanoma (A375) and human promyelocytic leukemia (HL60) cell lines. 2008 human ovarian cancer
cell line, was kindly provided by Prof. G. Marverti (Department of Biomedical Science, University of
Modena, Italy); A431 human cervix carcinoma was kindly provided by Prof. Zunino (Division of
Experimental Oncology B, Istituto Nazionale dei Tumori, Milan, Italy).
Cell lines were maintained in the logarithmic phase at 37°C in a 5% carbon dioxide atmosphere using
the following culture media: (i) RPMI-1640 medium (Euroclone, Celbio, Milan, Italy) containing 10%
foetal calf serum (Biochrom-Seromed GmbH & Co., Berlin, Germany) and supplemented with 25 mM
Hepes buffer, L-glutamine and with antibiotics penicillin (50 UmL−1) and streptomycin (50μgmL−1) for
HL60, 2008 and A431 cells; (ii) F-12 Ham’s (Sigma Chemical Co.) containing 10% foetal calf serum,
penicillin (50UmL−1) and streptomycin (50μgmL−1) for A549 cells; (iii) D-MEM (Dulbecco’s modified
Eagle’s medium) (Euroclone) supplemented with 10% foetal calf serum (Euroclone), penicillin
(50UmL−1) and streptomycin (50μgmL−1) for A375 cells.
1.13. Cytotoxicity assay
The growth inhibitory effect towards tumor cell lines was evaluated by means of MTT (tetrazolium salt
reduction) assay.345 Briefly, between 3–8×103cells, dependent upon the growth characteristics of the
cell line, were seeded in 96-well microplates in growth medium (100μL) and then incubated at 37°C in
a 5% carbon dioxide atmosphere. After 24h, the medium was removed and replaced with a fresh one
containing the compound to be studied at the appropriate concentrations. Triplicate cultures were
established for each treatment. Forty-eight hours later, each well was treated with 10μL of a 5mgmL−1
104
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) saline solution, and after 5h of
incubation, 100 μL of a sodium dodecylsulfate (SDS) solution in HCl 0.01M was added. After
overnight incubation, the inhibition of cell growth induced by the tested complexes was detected by
measuring the absorbance of each well at 570nm using a Bio-Rad microplate reader. Mean absorbance
for each drug dose was expressed as a percentage of the control untreated well absorbance and plotted
vs drug concentration. IC50 values represent the drug concentrations that reduced the mean absorbance
at 570nm to 50% of those in the untreated control wells.
2. Results and discussion
2.1. Synthesis and characterization of Cu(I) complexes
According to (Eq. (1)), Cu(I) complexes 1–5 have been obtained in high yield from the interaction of
one equivalent of the potassium salt K[H2B(tzNO2)2] with equimolar quantities of CuCl and two
equivalents of tertiary monophosphane PR3, in a methanol/acetonitrile (1:2) solution at room
temperature. The stoichiometry of these tetrahedral compounds (Fig. 37a) was not affected by reducing
(1 equivalent) or increasing (>2 equivalents) the amount of the relevant phosphane.
K[H2B(tzNO2)2]+CuCl+2PR3→[H2B(tzNO2)2]Cu[(PR3)2]+KCl
(1)
The reaction between K[H2B(tzNO2)2] and CuCl, carried in the presence of equimolar quantities of
bis(diphenylphosphane)ethane, dppe, under the conditions above detailed, yielded the mononuclear
complex 6 (Eq. (2))
K[H2B(tzNO2)2] + CuCl + dppe
[H2B(tzNO2)2]Cu(dppe) + KCl
(2)
The use of an excess of the chelate phosphane did not change the stoichiometry of the resulting
tetrahedral com plex (Fig. 37c).
105
Fig. 37. Proposed structure of derivatives 1–8. (a): (1) PR3 = tris(m-tolyl)phosphane; (2) PR3 = tris(p-tolyl)phosphane; (3)
PR3 = (p-diphenylphosphane)benzoic acid; (4) PR3 = tribenzylphosphane; (5) PR3 = tris(p-fluorophenyl)phosphane. (b): (7)
PR3 = tri(phenyl)phosphane selenide; (8) PR3 = tricyclohexylphosphane. (c): structure of derivative (6).
Analogously, 1:1:1 N-donor:copper:triorganophosphane Cu(I) complexes 7 and 8 have been prepared
in high yield from the interaction of equimolar amounts of the potassium salt K[H2B(tzNO2)2], CuCl and
tri(phenyl)phosphane selenide or tricyclohexylphosphane, in a methanol/acetonitrile (1:2) solution at
room temperature. Also in this case, the use of an excess of the relevant phosphane did not change the
stoichiometry of the resulting trigonal complexes (Fig.37b, Eq. (3)).
K[H2B(tzNO2)2]+CuCl+PR3→[H2B(tzNO2)2]Cu(PR3)+KCl
(3)
All of the colorless compounds 1–7 are soluble in CHCl3, acetone and DMSO, in which they are nonelectrolytes. Derivatives 1, 3 and 5 are soluble in water. Derivative 8 is only soluble in DMSO.
The infrared spectra show all the bands required by the presence of the organic nitrogen and the
phosphane ligands. In detail, for all copper derivatives 1–8 of [H2B(tzNO2)2] the B–H stretching mode
generally appears as broad peaks in the region 2419–2441cm−1, suggesting bidentate coordination of
the triazole ligand.176 For comparison, the B–H stretching appears in the 2469–2440cm−1 region in the
potassium salt of the free ligand, K[H2B(tzNO2)2]. Moreover, the asymmetric and symmetric stretching
of the –NO2 group moves from 1538 and 1304 cm−1 to the 1521–1548cm−1 and 1333–1377cm−1 ranges
ongoing from uncoordinated to coordinated ligand.
In the far-IR spectra of all derivatives 1–8, I have assigned the broad bands near 500cm−1 to Whiffen’s
y and t vibrations,283,346 respectively, on the basis of a previous report on phosphane copper(I)
106
complexes. In some cases weak to medium bands at ca. 300 cm−1 are observed. They are similar to
those described for silver–azolato complexes,193,347 which have been tentatively assigned to ν(Cu–N)
stretching vibrations.
The 1H NMR spectra of complexes 1–8, in chloroform, DMSO or methanol solution, show only one set
of resonances for H(5) protons, indicating that all triazole rings are equivalent; all the resonances are
slightly shifted in comparison with those of the potassium salt of the free ligand.343 The phosphane coligands show a characteristic series of resonances in the aromatic region. These evidences suggest
highly fluxional species or complete dissociation and reassociation of the triazole nitrogens.
The room temperature
31
P NMR spectra of complexes 1–6 and 8 show always a single broad
resonance, ascribed to some fluxional behavior in these complexes. Every free phosphine appears
upfield of its corresponding copper(I) complex. In the 31P NMR spectrum of 1–3 and 5 only one broad
peak is observed at 293K. No significant variations are detected in the
31
P NMR profiles on lowering
the temperature. At 223K, the signals fall in the range −4.81 to 0.78ppm, typical of a tetrahedral
N2CuP2 coordination core (Fig. 37a).348
The room temperature
31
P NMR spectra of complex 4, in chloroform solution, exhibits a broadened
signal centered at 1.20 ppm. Low temperature
31
P NMR spectra of complex 4 show sharp signals at
−8.41, −3.05 and 6.09 ppm, consistent with the occurrence of equilibria such as (4):
[H2B(tzNO2)2]Cu[P(CH2C6H5)3]2
[H2B(tzNO2)2]Cu[P(CH2C6H5)3]+P(CH2C6H5)3
(4)
An additional signal 45.07 ppm is assignable to the oxidized form of the free phosphane co-ligand.304
The room temperature 31P NMR spectra of [H2 B(tzNO2)2]Cu[dppe] (6), in chloroform solution, exhibits
a broadened signal centered at −0.98 ppm, compared with the sharp absorption at 0.66 ppm exhibited in
the spectra recorded at 223 K; such values are typical of mononuclear copper(I) species with CuN2P2
environments, suggesting a chelating coordination mode for the dppe ligand (Fig.37c).261 The room
temperature 31P NMR spectra of complex 7, in DMSO solution, exhibits a broadened signal centered at
29.10 ppm, assignable to the oxidized form of the free phosphane co-ligand.
2.2. Cytotoxicity results
The complexes [H2B(tzNO2)2]Cu[P(m-tolyl)3]2, 1, [H2B(tzNO2)2]Cu[P(C6H5)2(p-C6H4COOH)]2, 3, and
[H2B(tzNO2)2]Cu[P(p-C6H4F)3]2, 5, and the corresponding uncoordinated ligands were examined for
their cytotoxic properties against a panel of five human tumor cell lines containing examples of ovarian
107
(2008), cervix (A431) and lung (A549) cancer, melanoma (A375) and leukemia (HL60). For
comparison purpose, the cytotoxicity of cisplatin was evaluated under the same experimental
conditions. IC50 values, calculated from the dose–survival curves obtained after 48 h drug treatment
from MTT test, are shown in Table 5. All free ligands proved to be quite ineffective in all tumor cell
lines. Only P(p-C6H4F)3 and P(m-tolyl)3 ligands gave detectable IC50 values that were at least 15-fold
higher than those of the corresponding copper(I) complexes. Complex 3 showed IC50 values roughly
comparable to those exhibited by cisplatin, while complexes 1 and 5 were appreciably more effective
against all cell lines with respect to the reference metallodrug.
Table 5.
Cytotoxic activity
Compound
IC50 (μM) ± SD
2008
HL60
A431
A549
A375
[H2B(tzNO2)2]Cu[P(m-tolyl)3]2 (1)
10.11 ± 2.4
4.81 ± 0.9
6.7 ± 1.2
1.52 ± 0.7
16.4 ± 0.9
[H2B(tzNO2)2]Cu[P(C6H5)2(p-C6H4COOH)]2 (3)
14.31 ± 1.9
25.13 ± 1.2
15.25 ± 1.7
6.88 ± 2.0
35.15 ± 2.4
[H2B(tzNO2)2] Cu[P(p-C6H4F)3]2 (5)
5.60 ± 0.5
4.69 ± 1.2
3.66 ± 1.1
2.35 ± 0.9
4.33 ± 1.3
K[H2B(tzNO2)2]
ND
ND
ND
ND
ND
P(p-C6H4F)3
77.09 ± 1.9
65.23 ± 2.0
88.28 ± 2.9
68.12 ± 3.1
69.23 ± 1.0
P[(C6H5)2(p-C6H5COOH)]
ND
ND
ND
ND
ND
P(m-tolyl)3
60.4 ± 2.7
58.6 ± 3.1
66.9 ± 2.9
71.6 ± 2.8
55.3 ± 2.9
Cisplatin
12.69 ± 1.0
19.9 ± 2.5
22.06 ± 1.6
39.27 ± 1.9
20.28 ± 1.3
ND, not detectable.
SD, standard deviation.
IC50 values were calculated by probit analysis (P<0.05, χ2 test). Cells (3–8×103mL−1) were treated for 48h with increasing
concentrations of tested compounds. Cytotoxicity was assessed by MTT test.
In particular, on lung adenocarcinoma (A549) cells, that are intrinsically resistant to cisplatin,
cytotoxicities shown by complexes 1 and 5 exceeded that of cisplatin by a factor of about 20; this result
is encouraging as we could consider these new derivatives as lead compounds to develop new potential
drugs against lung carcinoma. The remarkable cytotoxic activity of 1 and 5 might be related to the
108
higher lipophilic character of these species compared to that of complex 3. In the latter case, the
presence of two benzoic groups in the outer sphere, that are known to be ionized at the physiological
pH value utilized in this study,349-351 tunes the hydro/lipophilic balance of the complex, thus influencing
and eventually reducing its cellular uptake. Although the mechanism of the antitumor activity exhibited
by these new copper(I) complexes remains unknown, it could be tentatively supposed that they may
uncouple oxidative phosphorylation by dissipation of the mitochondrial membrane potential, as
previously reported for similar Cu(I) complexes. In the latter study, it has been further noted that the
mitochondrial uptake of metal phosphane complexes is proportional to lipophilicity, making moderate
lipophilic complexes more active than hydrophilic ones. This statement is in full agreement with the
experimental evidences collected during this investigation.
Further studies are in progress to elucidate the mechanism of action of this new class of copper(I)
mixed ligand complexes.
109
Chapter 7
Silver(I)-organophosphane complexes of the
dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand
In this session I will put the accent on the synthesis of new silver(I) complexes by the interaction of
AgNO3, monodentate or bidentate tertiary phosphanes, and potassium dihydrobis(3-nitro-1,2,4triazolyl)borate, K[H2B(tzNO2)2] (see Chapter 5).343 These compounds have been characterized by
elemental analyses, FT-IR, ESI-MS and multinuclear (1H and
31
P) NMR spectral data. The adduct
{[H2B(tzNO2)2]Ag[P(m-tolyl)3]2} has been characterized by single crystal X-ray studies. In the former,
the H2B(tzNO2)2 acts as a monodentate ligand utilizing the coordinating capability of only one of the
additional (exo-) ring nitrogens to complete the coordination array about the silver atom.
1. Materials and methods
1.1. General procedures
All syntheses and handling were carried out under an atmosphere of dry oxygen-free dinitrogen, using
standard Schlenk techniques or a glove box. All solvents were dried, degassed and distilled prior to use.
Elemental analyses (C,H,N,S) were performed in house with a Fisons Instruments 1108 CHNS-O
Elemental Analyser. Melting points were taken on an SMP3 Stuart Scientific Instrument. IR spectra
were recorded from 4000 to 100cm−1 with a Perkin–Elmer System 2000 FT-IR instrument. IR
annotations used: m = medium, mbr = medium broad, s = strong, sbr = strong broad, sh = shoulder, w =
weak. 1H and 31P NMR spectra were recorded on a Oxford-400 Varian spectrometer (400.4 MHz for 1H
and 162.1 MHz for 31P). NMR annotations used: d = doublet, dd = double doublet, dbr = broad doublet,
m = multiplet, m = broad multiplet, s = singlet, sbr = broad singlet, t = triplet. Electrospray mass
spectra (ESIMS) were obtained in positive- or negative-ion mode on a Series 1100 MSD detector HP
spectrometer, using an acetone mobile phase. The compounds were added to the reagent grade
110
methanol to give solutions of approximate concentration of 0.1 mM. These solutions were injected
(1μl) into the spectrometer via a HPLC HP 1090 Series II fitted with an autosampler. The pump
delivered the solutions to the mass spectrometer source at a flow rate of 300 μlmin−1, and nitrogen was
employed both as a drying and nebulizing gas. Capillary voltages were typically 4000 and 3500 V for
the positive- and negative-ion mode, respectively. Confirmation of all major species in this ESIMS
study was aided by comparison of the observed and predicted isotope distribution patterns, the latter
calculated using the ISOPRO 3.0 computer program.
2. Experimental section
2.1. Synthesis
All reagents were purchased from Aldrich and used without further purification. The ligand potassium
dihydrobis(3-nitro-1,2,4-triazol-1-yl)borate K[H2B(tzNO2)2] was synthesised in accordance with the
literature method.343
{[H2B(tzNO2)2]Ag[P(o-tol)3]} (1). To a methanol solution (40°ml) of AgNO3 (0.170 g, 1.0 mmol) and
tris(o-tolyl)phosphane (0.304 g, 1.0 mmol), stirred for 3 h, K[H2B(tzNO2)2] (0.278 g, 1.0 mmol) was
added at room temperature. After the addition, the reaction mixture was stirred for 3 h, the solvent was
removed under vacuum. The resulting solid was dissolved in chloroform, the KNO3 was removed by
filtration and the residue was purified by re-crystallization from CHCl3/n-hexane (1:5) giving complex
1 as a microcrystalline white powder in 65% yield. M.p. 81 C dec. 1H NMR (CDCl3, 293 K): δ 2.50 (s,
9H, CH3), 6.84 (m, 3H, CH), 7.17 (m, 3H, CH), 7.30 (t, 3H, CH), 7.46 (t, 3H, CH), 8.20 (s, 2H, 5-CH).
1
H NMR (CDCl3, 223 K): δ 2.47 (s, 9H, CH3), 6.80 (br, 3H, CH), 7.19 (br, 3H, CH), 7.31 (br, 3H, CH),
7.44 (br, 3H, CH), 8.21 (br, 2H, 5-CH).
31
P NMR (CDCl3, 293 K): δ −18.09 (dbr, 1J(31P–
Ag) = 659 Hz). 31P NMR (CDCl3, 223 K): δ −20.18 (d, 1J(31P–Ag) = 726 Hz). IR (nujol, cm−1): 3163w,
3124w (CH), 2395m (BH), 1543s (C
C+C
N), 1505sh (νasym N–O), 1304m (νsym N–O), 565s,
559sh (NO2), 532m, 519m, 464s, 444sh (R3P), 400w, 386w, 377w, 325w, 280w. ESIMS (major
positive ions, CH3OH), m/z (%): 717 (100) [Ag{P(o-tol)3}2]+. ESIMS (major negative ions, CH3OH),
m/z (%): 239 (100) [H2B(tzNO2)2]−. Anal. Calc. for C25H25AgBN8O4P: C, 46.11; H, 3.87; N, 17.21.
Found: C, 45.78; H, 4.07; N, 17.10%.
111
{[H2B(tzNO2)2]Ag[P(m-tol)3]2} (2). Complex 2 was prepared analogously to compound 1 by using
AgNO3 (0.170 g, 1.0 mmol), tris(m-tolyl)phosphane (0.609 g, 2.0 mmol) and K[H2B(tzNO2)2] (0.278 g,
1.0 mmol). The product was obtained by re-crystallization from CHCl3/n-hexane (1:3), in 78% yield.
Crystals suitable for X-ray determination were obtained by slow evaporation of the solvent by a
chloroform/n-hexane solution of 2. M.p. 163–164 C. 1H NMR (CDCl3, 293 K): δ 2.15 (s, 18H, CH3),
7.02–7.21 (m, 24H, CH), 8.06 (s, 2H, 5-CH). 1H NMR (CDCl3, 223 K): δ 2.12 (s, 18H, CH3), 6.97–
7.20 (m, 24H, CH), 8.12 (sbr, 2H, 5-CH). 1H NMR (CDCl3, 193 K): δ 2.05 (s, 18H, CH3), 6.94–7.19
(m, 24H, CH), 8.21 (s, 1H, 5-CH), 8.42 (s, 1H, 5-CH).
31
P NMR (CDCl3, 293 K): δ 11.19 (br).
31
P
NMR (CDCl3, 223 K): δ 11.44 (dd, 1J(31P–109Ag) = 510 Hz, 1J(31P–107Ag) = 451 Hz). IR (nujol, cm−1):
3176m (CH), 2417mbr (BH), 1563m (C
C+C
N), 1524m (νasym N–O), 1301m (νsym N–O), 548s,
540sh, 524w (NO2), 464sh, 456s, 449sh, 430m (R3P), 378w, 352w, 280w. ESIMS (major positive ions,
CH3OH), m/z (%): 717 (100) [Ag{P(m-tol)3}2]+. ESIMS (major negative ions, CH3OH), m/z (%): 239
(100) [H2B(tzNO2)2]−. Anal. Calc. for C46H46AgBN8O4P2: C, 57.82; H, 4.85; N, 11.73. Found: C, 57.47;
H, 4.53; N, 11.44%.
{[H2B(tzNO2)2]Ag[P(p-tol)3]2} (3). Complex 3 was prepared analogously to compound 1 by using
AgNO3 (0.170 g, 1.0 mmol), tris(p-tolyl)phosphane (0.609 g, 2.0 mmol) and K[H2B(tzNO2)2] (0.278 g,
1.0 mmol). The product was obtained by re-crystallization from CHCl3/n-pentane (1:5), in 75% yield.
M.p. 149–150 C. 1H NMR (CDCl3, 293 K): δ 2.38 (s, 18H, CH3), 7.26–7.52 (m, 24H, CH), 8.22 (s, 2H,
5-CH). 1H NMR (CDCl3, 223 K): δ 2.39 (s, 18H, CH3), 7.28–7.55 (mbr, 24H, CH), 8.24 (sbr, 2H, 5CH).
109
31
P NMR (CDCl3, 293 K): 10.01 (br).
31
P NMR (CDCl3, 223 K): 8.03 (dd,
1
J(31P–
Ag) = 505 Hz, 1J(31P–107Ag) = 439 Hz). IR (nujol, cm−1): 3123w (CH), 2421m (BH), 1596m (C
C+C
N), 1537sbr (νasym N–O), 1304s (νsym N–O), 512sbr (NO2), 458w, 421mbr (R3P), 399w, 351w,
323w, 280w. ESIMS (major positive ions, CH3OH), m/z (%): 674 (100) [{H2B(tzNO2)2}Ag{P(ptol)3} + Na]+, 717 (20) [Ag{P(p-tol)3}2]+. ESIMS (major negative ions, CH3OH), m/z (%): 239 (100)
[H2B(tzNO2)2]−. Anal. Calc. for C46H46AgBN8O4P2: C, 57.82; H, 4.85; N, 11.73. Found: C, 58.07; H,
5.03; N, 11.50%.
{[H2B(tzNO2)2]Ag[P(p-C6H4F)3]2} (4). Complex 4 was prepared analogously to compound 1 by using
AgNO3 (0.170 g, 1.0 mmol), tris(p-fluorophenyl)phosphane (0.633 g, 2.0 mmol) and K[H2B(tzNO2)2]
(0.278 g, 1.0 mmol). The product was obtained by re-crystallization from diethyl ether/n-hexane (1:5),
in 74% yield. M.p. 60 C dec. 1H NMR (CDCl3, 293 K): δ 6.95–7.15 (m, 24H, CH), 8.20 (s, 2H, 5-CH).
112
1
H NMR (CDCl3, 223K): δ 6.99–7.16 (m, 24H, CH), 8.23 (s, 2H, 5-CH).
7.85 (d, 1J(31P–Ag) = 470 Hz).
107
31
31
P NMR (CDCl3, 293 K):
P NMR (CDCl3, 223 K): 6.95 (dd, 1J(31P–109Ag) = 505 Hz, 1J(31P–
Ag) = 441 Hz). IR (nujol, cm−1): 3062w (CH), 2422mbr (BH), 1587s (C
C+C
N), 1538s (νasym
N–O), 1300s (νsym N–O), 524sbr (NO2), 464m, 441s, 433sh, 403m (R3P), 376w, 352w, 325w, 304w,
280w. ESIMS (major positive ions, CH3OH), m/z (%): 740 (100) [Ag{P(p-C6H4F)3}2]+. ESIMS (major
negative ions, CH3OH), m/z (%): 239 (100) [H2B(tzNO2)2]−. Anal. Calc. for C40H28AgBF6N8O4P2: C,
49.06; H, 2.88; N, 11.44. Found: C, 48.88; H, 3.04; N, 11.62%.
{[H2B(tzNO2)2]Ag[SeP(C6H5)3]2} (5). Complex 5 was prepared analogously to compound 1 by using
AgNO3 (0.170 g, 1.0 mmol), tri(phenyl)phosphane selenide (0.682 g, 2.0 mmol) and K[H2B(tzNO2)2]
(0.278 g, 1.0 mmol). The product was obtained by re-crystallization from diethyl ether/n-hexane (1:3),
in 60% yield. M.p. 65 C dec. 1H NMR (CDCl3, 293 K): δ 7.38–7.63 (m, 30H, CH), 7.97 (s, 2H, 5-CH).
1
H NMR (CDCl3, 223 K): δ 7.29–7.50 (m, 30H, CH), 7.94 (sbr, 2H, 5-CH). 31P NMR (CDCl3, 293 K):
34.89 (s). IR (nujol, cm−1): 3051m (CH), 2423mbr (BH), 1574w (C
C+C
N), 1538s (νasym N–O),
1299s (νsym N–O), 546sbr, 510s, 502s (NO2), 455w, 436mbr (R3P), 399w, 325w, 280w. ESIMS (major
positive ions, CH3OH), m/z (%): 790 (100) [Ag{SeP(C6H5)3}2]+. ESIMS (major negative ions,
CH3OH), m/z (%): 239 (100) [H2B(tzNO2)2]−. Anal. Calc. for C40H34AgBN8O4P2Se2: C, 46.68; H, 3.33;
N, 10.89. Found: C, 46.28; H, 3.30; N, 11.07%.
{[H2B(tzNO2)2]Ag(dppe)} (6). Complex 6 was prepared analogously to compound 1 by using AgNO3
(0.170 g, 1.0 mmol), bis(diphenylphosphane)ethane, dppe (0.398 g, 1.0 mmol), and K[H2B(tzNO2)2]
(0.278 g, 1.0 mmol). The product was obtained by re-crystallization from chloroform/diethyl ether, in
90% yield. M.p. 117 C dec. 1H NMR (CDCl3, 293 K): δ 2.45 (s, 4H, CH2), 7.20–7.50 (m, 20H, CH),
8.25 (s, 2H, 5-CH). 1H NMR (CDCl3, 223 K): δ 2.39 (br, 4H, CH2), 7.23–7.52 (br, 20H, CH), 8.20 (br,
2H, 5-CH).
31
P NMR (CDCl3, 293 K): 9.10 (br).
31
P NMR (CDCl3, 223 K): 11.11 (br). IR (nujol,
cm−1): 3128w, 3052w (CH), 2428mbr (BH), 1586w (C
C+C
N), 1544s (νasym N–O), 1303s (νsym
N–O), 512s (NO2), 482s, 450m, 421w (R3P), 337w, 280w. ESIMS (major positive ions, CH3OH), m/z
(%): 905 (100) [Ag(dppe)2]+. ESIMS (major negative ions, CH3OH), m/z (%): 239 (100)
[H2B(tzNO2)2]−. Anal. Calc. for C30H28AgBN8O4P2: C, 48.35; H, 3.79; N, 15.04. Found: C, 48.21; H,
3.85; N, 14.84%.
113
{[H2B(tzNO2)2]Ag(dppf)} (7). Complex 7 was prepared analogously to compound 1 by using AgNO3
(0.170 g, 1.0 mmol), bis(diphenylphosphane)ferrocene, dppf (0.554 g, 1.0 mmol), and K[H2B(tzNO2)2]
(0.278 g, 1.0 mmol). The product was obtained by re-crystallization from chloroform, in 66% yield.
M.p. 159 C dec. 1H NMR (CDCl3, 293 K): 4.20–4.41 (m, 8H, CH), 7.30–7.50 (m, 20H, CH), 8.24 (s,
2H, 5-CH). 1H NMR (CDCl3, 223K): 4.42 (br, 8H, CH), 7.26–7.40 (m, 20H, CH), 8.31 (br, 2H, 5-CH).
P NMR (CDCl3, 293K): δ −2.60 (br). 31P NMR (CDCl3, 223 K): δ −3.50 (d, 1J(31P–Ag) = 437 Hz). IR
31
(nujol, cm−1): 3073w (CH), 2426mbr (BH), 1586w (C
C+C
N), 1538s (νasym N–O), 1300s (νsym
N–O), 539m, 512s (NO2), 499sh, 483s, 460s, 429m (R3P), 398w, 340w, 280w. ESIMS (major positive
ions, CH3OH), m/z (%): 662 (100) [Ag(dppf)]+, 1217 (100) [Ag(dppf)2]+, 1360 (60)
[Ag(dppf)2 + AgCl]+. ESIMS (major negative ions, CH3OH), m/z (%): 239 (100) [H2B(tzNO2)2]−. Anal.
Calc. for C38H32AgBFeN8O4P2: C, 50.65; H, 3.58; N, 12.43. Found: C, 50.24; H, 3.79; N, 12.11%.
2.2. X-ray structure determination for {[H2B(tzNO2)2]Ag[P(m-tol)3]2} (2)
Crystal data for complex (2). C46H46O4N8P2BAg: M = 955.53, monoclinic, space group P21/n,
a = 18.442(3), b = 16.113(3), c = 15.827(3) Å, β = 91.50(3), V = 4702(1) Å3, Z = 1, Dc = 1.350 g cm−3.
λ(Mo Kα) = 0.71073 Å, μ(Mo Kα) = 0.547 mm−1, F(000) = 1968. Crystals were lodged in Lindemann
glass capillary and centered on a four circle Philips PW1100 diffractometer using graphite
monochromated Mo Kα radiation (0.71073 Å), following the standard procedures at room temperature.
There were no significant fluctuations of intensities other than those expected from Poisson statistics.
All intensities were corrected for Lorentz polarization and absorption. The structures were solved by
standard direct methods.352 Refinement was carried out by full-matrix least-squares procedures (based
on
) using anisotropic temperature factors for all non-hydrogen atoms. Hydrogen atoms were
introduced at calculated positions in their described geometries and during refinement were allowed to
ride on the attached carbon atoms with fixed isotropic thermal parameters (1.2 Uequiv. of the parent
carbon atom). For a total of 565 parameters,
,
S = 1.174, and conventional R = 0.084, based on the F values of 6688 reflections having I
Structure refinement and final geometrical calculations were carried out with
SHELXL-97353
2σ(I).
program,
implemented in the WinGX package.
114
3. Results and discussion
3.1. Syntheses
According to Eq. (1), the 1:1:1 N-donor:silver:triorganophosphane Ag(I) complex 1 has been prepared
in high yield from the interaction of equimolar amounts of the potassium salt K[H2B(tzNO2)2], AgNO3
and tris(o-tolyl)phosphane, in a methanol solution at room temperature. The use of an excess of the
relevant phosphane did not change the stoichiometry of the resulting trigonal complexes (Eq. (1))
K[H2B(tzNO2)2] + AgNO3 + P(o-tolyl)3 →{[H2B(tzNO2)2]Ag[P(o-tolyl)3)]} + KNO3
(1)
Analogously, 1:1:2 N-donor:silver:triorganophosphane Ag(I) complexes 2-5 have been obtained in
high yield from the interaction of one equivalent of the potassium salt K[H2B(tzNO2)2] with equimolar
quantities of AgNO3 and two equivalents of tertiary monophosphane PR3, in a methanol solution at
room temperature. Also in this case, the stoichiometry of the compounds was not affected by reducing
(1 equiv.) or increasing (>2 equiv.) the amount of the relevant phosphane (Eq. (2)).
K[H2B(tzNO2)2] + AgNO3 + 2PR3 →{[H2B(tzNO2)2]Ag[(PR3)2]} + KNO3
2-5
(2)
The reaction between K[H2B(tzNO2)2] and AgNO3, carried out in the presence of equimolar quantities
of bis(diphenylphosphane)ethane, dppe, or bis(diphenylphosphane)ferrocene, dppf, under the
conditions detailed above, yielded mononuclear complexes 6 and 7 (Eq. (3))
K[H2B(tzNO2)2] + AgNO3 + dppx →{[H2B(tzNO2)2]Ag(dppx)} + KNO3
(3)
The use of an excess of the chelate phosphane did not change the stoichiometry of the resulting
complex.
All of the colourless compounds 1–7 are soluble in CHCl3, methanol, acetone and DMSO and they are
insoluble in water, diethyl ether and aliphatic or aromatic hydrocarbon solvents.
115
3.2. Spectroscopy
The infrared spectra show all the bands required by the presence of the organic nitrogen and the
phosphane ligands. In detail, the derivative {[H2B(tzNO2)2]Ag[P(o-tolyl)3]} (1) exhibits he BH
stretching at 2395 cm−1. For silver derivatives 2–7, the B–H stretching modes appear as broad peaks in
the region 2417–2428 cm−1. For comparison, the B–H stretching appears in the 2469–2440 cm−1 region
in the potassium salt of the free ligand, K[H2B(tzNO2)2]. Moreover, the asymmetric and symmetric
stretching of the –NO2 group moves from 1538 and 1304 cm−1 to the 1505–1544 and 1299–1304 cm−1
ranges ongoing from uncoordinated to coordinated ligand. The infrared spectrum of derivative 1,
{[H2B(tzNO2)2]Ag[P(o-tolyl)3]}, is different from those of the 1:1:2 N-donor:silver:triorganophosphane
Ag(I) complexes 2–7, suggesting a different coordination of the scorpionate ligand. In particular, the
NO2-rocking vibration appears at 565 cm−1 as a strong vibration in compound 1, while medium or
strong absorptions are observed in the range 502–548 cm−1 in the spectra of derivatives 2–7. This
behaviour is in accordance with the absence of relevant interactions of the NO2 group of oxygen atoms
in all derivatives. In the far-IR spectra of all derivatives 1–7, we have assigned the broad bands near
500 cm−1 to Whiffen’s y and t vibrations,283,346 respectively, on the basis of a previous report on
phosphane copper(I) and silver(I) complexes.176
The room temperature 1H NMR spectra of complexes 1–7, in chloroform or methanol solution, show
only one set of resonances for H(5) protons, indicating that all the triazole rings are equivalent; all the
resonances are slightly shifted in comparison with those of the potassium salt of the free ligand.343 The
phosphane coligands show a characteristic series of resonances in the aromatic region. These evidences
suggest highly fluxional species or complete dissociation and reassociation of the triazole nitrogens.
Variable temperature 1H NMR studies have been done for all the complexes. For derivative 1 no
significant variations are detected in the 1H NMR profiles on lowering the temperature, while for
complexes 2–7 it was possible to slow down the rate of the dynamic process responsible for the
spectrum obtained at room temperature: at 223 K the spectra always show a broadening of the triazole
proton resonances and at 193 K a static spectrum was obtained for derivative 2. This pattern indicates
that the two triazolyl rings are magnetically different according to the solid state structure of compound
2.
In the 31P NMR spectrum of {[H2B(tzNO2)2]Ag[P(o-tol)3]} (1), a doublet is observed at −18.09 ppm at
293 K and at −20.18 ppm at 223 K, with coupling constants typical of a monophosphane species
and.348 In the
31
P NMR spectra of derivatives 2–4, only one peak is observed at 293 K and a double
doublet at 223 K with coupling constants 1J(107Ag–31P) in the range 439–451 Hz and 1J(109Ag–31P) in
116
the range 505–510 Hz, both typical of a diphosphane species. A similar behavior has been found for the
dppf complex 7 for which the coupling constant found at low temperature is typical of a AgP 2
coordination core.
The spectroscopic data suggest for derivative 1 an AgN2P central core in which the ligand coordinates
in bidentate κ2-N(2),N′(2) mode (Fig. 38) and for derivatives 2–7 an AgNP2 central core in which the
ligand coordinates in monodentate κ1-N(2) or κ1-N(4) mode (Fig. 39), the second one in accordance
with the crystal structure of {[H2B(tzNO2)2]Ag[P(m-tol)3]2} (2) (Fig. 40).
Fig. 38. Proposed structure of derivative 1.
Fig. 39. Proposed structure of derivatives 2–7.
117
Fig. 40. The molecular structure of complex 2.
Electrospray ionization mass spectroscopy was used to probe the existence of aggregates of the
scorpionate ligand with Ag(I) and phosphane coligand in solution. Both positive-ion and negative-ion
spectra of complexes 1–7, dissolved in methanol, were recorded at low voltage (3.5–4.0 kV); under
these experimental conditions the dissociation is minimal and most of the analyte is transported to the
mass spectrometer as the intact molecular species. The negative-ion spectra of compounds 1–7 were
dominated by the fragment at m/z 239 (100%) due to the free scorpionate ligand, [H2B(tzNO2)2]−. The
positive-ion spectra of all the triorganophosphane derivatives 1–4 were dominated by the fragments
[Ag(PR3)2]+; analogously the main peak in the spectra of compound 5 is [Ag{SeP(C6H5)3}2]+ at m/z
790 (100%). Only in the positive-ion spectrum of compound 3 we observed at m/z 674 (100%) the peak
due to the aggregate [{H2B(tzNO2)2}Ag{P(p-tol)3} + Na]+, together with the minor peak at m/z 717
(20%) attributable to the ion [Ag{P(p-tol)3}2]+ generated by the loss of scorpionate ligand. The
positive-ion spectrum of derivative 6 was dominated by the fragment [Ag(dppe)2]+ at m/z 905 (100%).
In the positive-ion spectrum of compound 7, we observed at m/z 662 (100%) the peak due to the
aggregate [Ag(dppf)]+, at m/z 1217 (100%) the peak due to the aggregate [Ag(dppf)2]+ and at m/z 1360
(60%) a minor peak attributable to the cluster [Ag(dppf)2 + AgCl]+.
118
3.3. X-ray crystallography
Fig. 41. The molecular structure of complex {[H2B(tzNO2)2]Ag[P(m-tol)3]2}
The ORTEP representation and the numbering scheme of the complex {[H2B(tzNO2)2]Ag[P(m-tol)3]2}
(2) are shown in Fig. 41, selected bond lengths and angles are listed in Table 6. The silver(I) atom is
three coordinated in a distorted trigonal P2N environment with a slight compression of the N–Ag–P
angles (108.1(2) averaged value) and enlargement of the P–Ag–P angle (142.5(7)). The deviation from
the ideal trigonal geometry is likely due to the large steric hindrance of the P(m-tol)3 co-ligands in
connection with the monodentate binding mode of [H2B(tzNO2)2] ligand.
Table 6. Selected interatomic bond lengths (Å) and angles (°) for {[H2B(tzNO2)2]Ag[P(m-tol)3]2} (2)
bond lengths (Å)
Ag–P(1)
2.444(2)
Ag–P(2)
2.458(2)
Ag–N(1)
2.364(6)
N(1)–C(1)
1.336(9)
N(1)–C(2)
1.327(9)
N(2)–N(3)
1.365(9)
N(2)–C(2)
1.331(9)
N(3)–C(1)
1.308(9)
N(4)–O(1)
1.213(8)
N(4)–O(2)
1.224(8)
N(4)–C(1)
1.441(9)
N(5)–N(6)
1.353(9)
N(5)–C(4)
1.332(9)
N(6)–C(3)
1.353(9)
119
bond lengths (Å)
N(7)–C(3)
1.330(9)
N(7)–C(4)
1.334(9)
B–N(2)
1.56(1)
B–N(5)
1.56(1)
N(8)–O(3)
1.217(9)
N(8)–O(4)
1.212(9)
N(8)–C(3)
1.447(9)
bond angles (°)
P(1)–Ag–P(2)
142.5(7)
N(1)–Ag–P(2)
104.6(2)
N(1)–Ag–P(1)
111.5(7)
C(1)–N(1)–Ag
127.7(5)
C(2)–N(1)–Ag
128.9(5)
N(5)–B–N(2)
107.7(7)
Recently, silver(I) complexes with triazolyl-borate and benzotriazolyl-borate ligands have shown an
enhanced capacity for the formation of unusual species, often oligo- or poly-meric in nature as a
consequence of the coordination ability of the exo nitrogen donors higher than their pyrazolyl and
imidazolyl counterparts. With H2Bpz2 ligands (Hpz = pyrazole), the predominant coordination mode is
chelation of the pair of available nitrogen donors, adjacent to the other nitrogen atoms bonded to the
boron, forming a six-membered ring, usually of boat conformation, with silver and boron at the prows.
It is therefore surprising to find a monodentate coordination mode of the ligand probably due to the
availability of the two additional P(m-tol)3 moieties. In addition, it is worthwhile noticing that of the
three available nitrogen atoms, the one remote from the boron is preferred in the metal coordination.
The Ag–P(1), Ag–P(2) and Ag–N(1) bond distances are 2.444(2), 2.458(2) and 2.364(6) Å,
respectively, with values comparable to those found in similar tris(pyrazolyl)borate ligand
complexes.263
The silver atom lies −0.155(1) Å out of the mean P(2)–N(1)–P(1) plane. The two nitro functionalities
of the ligand are coplanar to the respective triazolyl ring, while the latter is inclined 83.2(3) with
respect to the other.
Neutral complexes containing P2AgN three-coordinate environments are rather unusual; further
examples are the structures of
and
where
however the coordination geometries are closer to the ideal trigonal one, due to the minor steric
hindrance of the nitrogen donor ligands.354
120
Chapter 8
Silver(I)-organophosphane complexes of a highly
electron withdrawing nitro-substituted scorpionate
ligand
In Chapter 5 and 6 I reported respectively, the first successful synthesis of the heteroscorpionate
ligand, dihydridobis(3-nitro-1,2,4-triazolyl)borate, [H2B(tzNO2)2]-, and its copper(I) complexes.343 In
this session, the synthesis of a new dihydridobis(3-nitropyrazolyl)borate ligand, [H2B(pzNO2)2]- is
exposed. This ligand represents the 3-nitro-substituted analogue of one of most widely used
bis(pyrazolyl)borates,1 and could be of interest due to its peculiar steric and electronic properties and its
high coordinative flexibility (e.g., from 2-N2 to 4-N2O2). Experiments carried out over
[H2B(pzNO2)2]
-
showed that this ligand seemed to be a good ligand to stabilize silver(I) phosphine
complexes. It is noteworthy that the silver(I) complexes of dihydridobis(pyrazolyl)borates are relatively
uncommon.276 The reduction of Ag(I) to silver metal caused by the B-H moiety is a common problem
during their synthesis.
1. Experimental
1.1. Materials and general methods
All syntheses and handling were carried out under an atmosphere of dry oxygen-free dinitrogen, using
standard Schlenk techniques or a glove box. All solvents were dried, degassed and distilled prior to use.
Elemental analyses (C,H,N,S) were performed in house with a Fisons Instruments 1108 CHNS-O
Elemental Analyser. Melting points were taken on an SMP3 Stuart Scientific Instrument. IR spectra
were recorded from 4000 to 100 cm-1 with a Perkin-Elmer System 2000 FT-IR instrument. IR
annotations used: m = medium, mbr = medium broad, s = strong, sbr = strong broad, sh = shoulder, w =
weak. 1H-, and 31P-NMR spectra were recorded on a Oxford-400 Varian spectrometer (400.4 MHz for
121
1
H, and 162.1 MHz for
31
P). NMR annotations used: d = doublet, dd = double doublet, dbr = broad
doublet, m = multiplet, m = broad multiplet, s = singlet, sbr = broad singlet, t = triplet. Electrospray
mass spectra (ESIMS) were obtained in positive- or negative-ion mode on a Series 1100 MSD detector
HP spectrometer, using an acetone mobile phase. The compounds were added to the reagent grade
methanol to give solutions of approximate concentration 0.1 mM. These solutions were injected (1 l)
into the spectrometer via a HPLC HP 1090 Series II fitted with an autosampler. The pump delivered the
solutions to the mass spectrometer source at a flow rate of 300 l min-1, and nitrogen was employed
both as a drying and nebulizing gas. Capillary voltages were typically 4000 V and 3500 V for the
positive- and negative-ion mode, respectively. Confirmation of all major species in this ESIMS study
was aided by comparison of the observed and predicted isotope distribution patterns, the latter
calculated using the IsoPro 3.0 computer program.
1.2. Synthesis of the ligand
Potassium dihydrobis(3-nitro-pyrazol-1-yl)borate, K[H2B(pzNO2)2] (1). 1-nitro-pyrazole (3.00 g,
26.5 mmol) was solved in the minimum amount of anisole (7 ml); the solution was gradually heated up
to 145C and kept under stirring for 10 h. After being cooled, a white, crystalline solid precipitated from
the orange solution; to the mixture potassium borohydride, KBH4 (0.712 g, 13.2 mmol), was added at
80C with an instantaneous release of hydrogen. The solution was kept under stirring at this temperature
for 3 h, and then heated at 120°C for 5 h. The mixture was cooled at room temperature, treated with
diethyl ether (50 ml) and filtered off. The solution was concentrated under vacuum and treated with nhexane (100 ml) to precipitate a microcrystalline white solid. It was filtered, purified by recrystallisation from diethyl ether/n-hexane (1:5), and dried at reduced pressure to yield derivative 1 in
60% yield. Mp. 170°C dec. 1H NMR (DMSO, 293K):  6.75 (d, 2H, 4-CH), 7.60 (d, 2H, 5-CH). 1H
NMR (CD3OH, 293K):  6.74 (d, 2H, 4-CH), 7.62 (d, 2H, 5-CH).13C{1H}NMR (DMSO, 293K): 
101.39 (C4), 137.15 (C5), 156.59 (C3). IR (Nujol, cm-1): 3143w, 3122w (CH), 2423m, 2381m, 2266m,
2201w (BH), 1667m (C=C + C=N), 1530s (asym NO2), 1301s (sym NO2), 616m (NO2), 442m. ESIMS
(major negative-ions, CH3OH), m/z (%): 237 (100) [H2B(pzNO2)2]-. Calcd. for C6H6BKN6O4: C, 26.11;
H, 2.19; N, 30.44%. Found: C, 25.84; H, 2.28; N, 30.11%.
122
1.3. Syntheses of Silver complexes
{[H2B(pzNO2)2]Ag[P(C6H5)3]2} (2). To a methanol solution (20 ml) of AgNO3 (0.085 g, 0.5 mmol),
triphenylphosphine (0.262 g, 1.0 mmol) was added at room temperature and stirred for 4 h to give a
colorless solution and a white precipitate. A methanol solution (5 ml) of potassium dihydrobis(3-nitropyrazol-1-yl)borate, K[H2B(pzNO2)2] (0.138 g, 0.5 mmol) was added drop-wise to the previous mixture.
After addition, the reaction mixture was stirred for 4 h and the resulting white solid was filtered off and
re-crystallized from methanol/diethyl ether to give complex 2 in 72% yield. The crude complex 2 was
dissolved in methanol/diethyl ether solution and a single crystal suitable for X-ray diffraction analysis
was obtained. 1H NMR (CDCl3, 293K):  6.68 (d, 2H, 4-CH), 7.30-7.38 (m, 30H, C6H5), 7.52 (d, 2H,
5-CH). 31P NMR (CDCl3, 293K):  10.25 (s).
31
P NMR (CDCl3, 223K):  11.53 (d, 1J(31P-Ag) = 455
Hz). IR (nujol, cm-1): 3164w (CH), 2417m, 2380w (BH), 1535s (C=C + C=N), 1503m (asym NO2),
1303s (sym NO2), 617m (NO2), 542m, 512s, 500sbr, 487sbr (R3P). ESIMS (major positive-ions,
CH3OH), m/z (%): 632 (100) {Ag[P(C6H5)3]2}+. ESIMS (major negative-ions, CH3OH), m/z (%): 237
(100) [H2B(pzNO2)2]-. Anal. Calcd for C42H36AgBN6O4P2: C, 58.02; H; 4.17; N, 9.67. Found: C, 57.84;
H, 4.27; N, 9.35%.
{[H2B(pzNO2)2]Ag[P(o-C6H4CH3)3]} (3). Complex 3 was prepared analogously to compound 2 by
using AgNO3 (0.170 g, 1.0 mmol), tri(o-tolyl)phosphine, P(o-C6H4CH3)3 (0.304 g, 1.0 mmol), and
potassium dihydrobis(3-nitro-pyrazol-1-yl)borate K[H2B(pzNO2)2] (0.276 g, 1.0 mmol). The product
was re-crystallized from methanol/diethyl ether (1:5), affording derivative 3 in 82% yield. 1H NMR
(CDCl3, 293K):  2.52 (s, 9H, CH3), 6.78 (d, 2H, 4-CH), 6.86-7.41 (m, 12H, C6H4), 7.58 (d, 2H, 5CH). 31P NMR (CDCl3, 293K):  -16.70 (dd, J(31P-107Ag) = 653 Hz; J(31P-109Ag) = 742 Hz). IR (nujol,
cm-1): 3149w, 3125w, 3044w (CH), 2441m, 2364m (BH), 1588m, 1531s (C=C + C=N), 1489s (asym
NO2), 1306s (sym NO2), 615m (NO2), 565m, 558sh, 522m, 515m, 464s (R3P). ESIMS (major positiveions, CH3OH), m/z (%): 717 (100) {Ag[P(o-C6H4CH3)3]2}+. ESIMS (major negative-ions, CH3OH), m/z
(%): 237 (100) [H2B(pzNO2)2]-. Anal. Calcd for C27H27AgBN6O4P: C, 49.95; H; 4.19; N, 12.95. Found:
C, 49.93; H, 4.30; N, 12.54%.
{[H2B(pzNO2)2]Ag[P(m-C6H4CH3)3]} (4). To a methanol solution (20 ml) of AgNO3 (0.170 g, 1.0
mmol), tri(m-tolyl)phosphine, P(m-C6H4CH3)3 (0.304 g, 1.0 mmol), was added at room temperature
and stirred for 4 h to give a colorless solution and a white precipitate. A methanol solution (5 ml) of
123
potassium dihydrobis(3-nitro-pyrazol-1-yl)borate, K[H2B(pzNO2)2] (0.276 g, 1.0 mmol) was added
drop-wise to the previous mixture. After addition, the reaction mixture was stirred for 4 h and solvent
removed under vacuum. The resulting solid was treated with chloroform (50 mL) and salt removed by
filtration. The solution was concentrated under vacuum and a colorless solid was filtered off and recrystallized from CHCl3/diethyl ether (1:5) to give complex 4 in 66% yield. 1H NMR (CDCl3, 293K): 
2.31 (s, 9H, CH3), 6.81 (d, 2H, 4-CH), 7.25-7.40 (m, 12H, C6H4), 7.61 (d, 2H, 5-CH).
31
P NMR
(CDCl3, 293K):  16.50 (d, J(31P-Ag) = 697 Hz). 31P NMR (CDCl3, 223K):  15.81 (dd, J(31P-107Ag) =
660 Hz; J(31P-109Ag) = 762 Hz). IR (nujol, cm-1): 3142w, 3119w, 3041w (CH), 2453m, 2389m (BH),
1588m, 1530s (C=C + C=N), 1489s (asym NO2), 1307s (sym NO2), 614w (NO2), 548s, 538sh, 471m,
454s, 451s (R3P). ESIMS (major positive-ions, CH3OH), m/z (%): 717 (100) {Ag[P(m-C6H4CH3)3]2}+.
ESIMS (major negative-ions, CH3OH), m/z (%): 237 (100) [H2B(pzNO2)2]-. Anal. Calcd for
C27H27AgBN6O4P: C, 49.95; H; 4.19; N, 12.95. Found: C, 50.06; H, 4.35; N, 12.78%.
{[H2B(pzNO2)2]Ag[P(p-C6H4CH3)3]} (5). Complex 5 was prepared analogously to compound 2 by
using AgNO3 (0.170 g, 1.0 mmol), tri(p-tolyl)phosphine (0.304 g, 1.0 mmol) and potassium
dihydrobis(3-nitro-pyrazol-1-yl)borate, K[H2B(pzNO2)2] (0.276 g, 1.0 mmol). The product was recrystallized from methanol/diethyl ether (1:3), in 61% yield. The crude complex 5 was dissolved in
chloroform/diethyl ether solution and a single crystal suitable for X-ray diffraction analysis was
obtained. 1H NMR (CDCl3, 293K):  2.38 (s, 9H, CH3), 6.83 (d, 2H, 4-CH), 7.21-7.44 (m, 12H, C6H4),
7.62 (d, 2H, 5-CH).
31
P NMR (CDCl3, 293K):  14.42 (d, 1J(31P-Ag) = 699 Hz).
31
P NMR (CDCl3,
223K):  13.70 (dd, 1J(31P-107Ag) = 663 Hz; 1J(31P-109Ag) = 765 Hz). IR (nujol, cm-1): 3142w (CH),
2458m, 2386m (BH), 1597m, 1537s (C=C + C=N), 1495s (asym NO2), 1309s (sym NO2), 614m (NO2),
520s, 505s (R3P). ESIMS (major positive-ions, CH3OH), m/z (%): 717 (100) {Ag[P(p-C6H4CH3)3]2}+.
ESIMS (major negative-ions, CH3OH), m/z (%): 237 (100) [H2B(pzNO2)2]-. Anal. Calcd for
C27H27AgBN6O4P: C, 49.95; H; 4.19; N, 12.95. Found: C, 49.81; H, 4.32; N, 12.84%.
{[H2B(pzNO2)2]Ag[PCH3(C6H5)2]} (6). Complex 6 was prepared analogously to compound 4 by using
AgNO3 (0.170 g, 1.0 mmol), methyldiphenyl-phosphine, PCH3(C6H5)2 (0.200 g, 1.0 mmol) and
potassium dihydrobis(3-nitro-pyrazol-1-yl)borate, K[H2B(pzNO2)2] (0.276 g, 1.0 mmol). The product
was re-crystallized from chloroform/n-hexane (1:3) to give derivative 6 in 70% yield. 1H NMR (CDCl3,
293K):  1.87 (d, 3H, CH3), 6.73 (d, 2H, 4-CH), 7.30-7.45 (m, 10H, C6H5), 7.58 (d, 2H, 5-CH).
31
P
124
NMR (CDCl3, 293K):  -7.04 (s).
P NMR (CDCl3, 223K):  -6.90 (d, 1J(31P-Ag) = 590 Hz). IR
31
(nujol, cm-1): 3151w, 3147w, 3051w (CH), 2426m, 2412m (BH), 1585w, 1523m (C=C + C=N), 1483s
(asym NO2), 1298s (sym NO2), 617m (NO2), 498s, 479s (R3P). ESIMS (major positive-ions, CH3OH),
m/z (%): 508 (100) {Ag[P(CH3)(C6H5)3]2}+. ESIMS (major negative-ions, CH3OH), m/z (%): 237 (100)
[H2B(pzNO2)2]-. Anal. Calcd for C19H19AgBN6O4P: C, 41.87; H; 3.51; N, 15.42. Found: C, 41.64; H,
3.47; N, 15.25%.
1.4. X-ray data collection and structure determinations
A suitable crystal of each sample covered with a layer of hydrocarbon oil was selected and mounted
with paratone-N oil on a cryo-loop, and immediately placed in the low-temperature nitrogen stream.
The X-ray intensity data were measured at 100(2) K on a Bruker SMART APEX CCD area detector
system equipped with a Oxford Cryosystems 700 Series Cryostream cooler, a graphite monochromator,
and a Mo K fine-focus sealed tube (
as placed at a distance of 5.995
cm from the crystal. The data frames were integrated with the Bruker SAINT-Plus software package.
Data were corrected for absorption effects using a multi-scan technique (SADABS). Structures were
solved and refined using Bruker SHELXTL (Version 6.14) software package. K[H2B(pzNO2)2]
crystallizes in the monoclinic P21/c space group. The -angle (90.0730(10)°) was uncomfortably closer
to 90° indicating possible orthorhombic cell choice. However, data merging was relatively poor and the
structure solution was difficult when the orthorhombic cell was used as compared to the monoclinic
option. K[H2B(pzNO2)2] was solved in P21/c using direct methods. All the non hydrogen atoms were
refined anisotropically. Hydrogen atoms on the pyrazolyl rings and on boron were located from the
difference map and included, and refined isotropically. Final check using PLATON did not identify a
higher
symmetry
alternative.
The
silver
adducts
[H2B(pzNO2)2]Ag[P(C6H5)3]2
and
[H2B(pzNO2)2]Ag[P(p-C6H4CH3)3] crystallize in the monoclinic crystal system as well. Their structures
were solved using direct methods. All the non-hydrogen atoms were refined anisotropically. The
hydrogen atoms on boron were located from the difference map and included. Some details of the data
collection and refinement of K[H2B(pzNO2)2], [H2B(pzNO2)2]Ag[P(C6H5)3]2 and [H2B(pzNO2)2]Ag[P(pC6H4CH3)3] are given in Table 7.
125
Table 7. Crystal data and summary of data collection and refinement
Compound
1
2
5
Empirical formula
C6 H6 B K N6 O4
C42 H36 Ag B N6 O4 P2
C27 H27 Ag B N6 O4 P
Formula weight
276.08
869.39
649.2
Temperature
100(2) K
100(2) K
100(2) K
Wavelength
0.71073 Å
0.71073 Å
0.71073 Å
Crystal system
Monoclinic
Monoclinic
Monoclinic
Space group
P2(1)/c
P2(1)/n
C2/c
Unit cell dimensions
a = 6.4667(2) Å
a = 10.2087(7) Å
a = 35.4543(15) Å
b = 22.3304(8) Å
b = 20.5503(13) Å
b = 10.6701(5) Å
c = 7.5362(3) Å
c = 18.9869(12) Å
c = 15.0076(6) Å
Volume
1088.26(7) Å3
3935.6(4) Å3
5659.0(4) Å3
Z
4
4
8
Density (calculated)
1.685 Mg/m3
1.467 Mg/m3
1.524 Mg/m3
Absorption coefficient
0.506 mm-1
0.644 mm-1
0.813 mm-1
Reflections collected
8618
28835
22606
Independent reflections
2123 [R(int) = 0.0229]
7736 [R(int) = 0.0380]
5871 [R(int) = 0.0151]
Goodness-of-fit on F2
1.063
1.031
1.055
Final R indices [I>2sigma(I)] R1 = 0.0251, wR2 = 0.0666
R1 = 0.0325, wR2 = 0.0810
R1 = 0.0252, wR2 = 0.0664
R indices (all data)
R1 = 0.0374, wR2 = 0.0861
R1 = 0.0268, wR2 = 0.0677
R1 = 0.0256, wR2 = 0.0670
2. Results and discussion
2.1. Syntheses, consideration and general characterization
The 3(5)-nitropyrazole has been synthesized by thermal isomerization of 1-nitropyrazole in very high
yield (> 95%). The potassium salt of dihydridobis(3-nitropyrazolyl)borate, 1, has been synthesized by
treating KBH4 with 3-nitro-pyrazole in anisole solvent (Scheme 24).
126
H
H
N
N
145°C
N
KBH4, 120°C
N
Anisole
N
Anisole
N
NO2
H
B
O2N
O2N
>95%
N
N
K
NO2
[H2B(pzNO2)]K, 1
Scheme 24. Synthesis of compound 1
Compound 1 is an air- and moisture-stable colorless solid; it is soluble in all common organic and
protic solvents. According to eqn. 1, the 1:1:2 N-donor:silver:triorganophosphane Ag(I) complex 2 has
been obtained in high yield from the interaction of one equivalent of the potassium salt K[H 2B(pzNO2)2]
with equimolar quantities of AgNO3 and two equivalents of triphenylphosphane, in a methanol solution
at room temperature. The stoichiometry of the compound was not affected by reducing (1 equivalent)
or increasing (> 2 equivalents) the amount of the relevant phosphane.
K[H2B(pzNO2)2] + AgNO3 + 2 P(C6H5)3  {[H2B(pzNO2)2]Ag[P(C6H5)3]2} + KNO3
(1)
2
Analogously, the 1:1:1 N-donor:silver:triorganophosphane Ag(I) complexes 3-6 have been prepared in
high yield from the interaction of equimolar amounts of the potassium salt K[H2B(pzNO2)2], AgNO3 and
the tertiary monophosphane PR3, in a methanol solution at room temperature. The use of an excess of
the relevant phosphane did not change the stoichiometry of the resulting trigonal complexes (eqn. 2).
K[H2B(pzNO2)2] + AgNO3 + PR3  {[H2B(pzNO2)2]Ag[PR3]} + KNO3
3: PR3 = P(o-C6H4CH3)3
4: PR3 = P(m-C6H4CH3)3
5: PR3 = P(p-C6H4CH3)3
6: PR3 = PCH3(C6H5)2
(2)
The colourless compounds 2-6 are soluble in CHCl3, methanol, acetone and DMSO and they are
insoluble in water, diethyl ether and aliphatic or aromatic hydrocarbon solvents.
The potassium salt 1 and the complexes 2-6 have been characterized by 1H-,
31
P-NMR, FT-IR
spectroscopy, electrospray ionization mass spectroscopy (ESI-MS) and elemental analysis. In the
infrared spectrum of 1 the B-H stretching vibrations appears in the range 2423-2201 cm-1. Coordination
of B-H bonds to metal ions characteristically leads to lower B-H stretching frequencies. The IR data in
127
1 suggest the possible existence of a K-H-B agostic interaction which is confirmed by X-ray analysis.
The asymmetric and symmetric stretchings of -NO2 group appear at 1530 cm-1 and 1301 cm-1, in
accordance with the values generally found for C-nitro groups in nitropyrazoles (asym 1545-1490 cm-1,
sym 1375-1330 cm-1). The
13
C chemical shifts of 4-CH, 5-CH and 3-CNO2 carbons (in DMSO
solution) are at  101.39, 137.15 and 156.59 respectively; for comparison the
13
C chemical shift of 3-
CCF3 carbons is in the range 139.53-141.31 ppm in polyfluorinated scorpionate ligands65,67,241,355 and at
 144.01 in the K[BpCOOET,Me] ligand.
The infrared spectra of complexes 2-6 show all the bands required by the presence of the organic
bis(pyrazolyl)borate
and
the
phosphane
{[H2B(pzNO2)2]Ag[P(C6H5)3]2}, 2, exhibits
according
with
a
k2-N2
chelating
ligands.
For
example,
the
derivative
the BH stretching at 2417 cm-1 and 2380 cm-1 in
coordination
of
the
ligand.
For
1:1:1
N-
donor:silver:triorganophosphane Ag(I) complexes 3-6 the B-H stretching modes appear as broad peaks
in the region 2363-2458 cm-1, suggesting the same 2-N2 coordination of the scorpionate ligand.
Moreover, the asymmetric and symmetric stretching of the -NO2 group are at 1530 cm-1 and 1301 cm-1
in the free ligand and the ranges 1523-1537 and 1298-1309 cm-1 in derivatives 2-6; moreover the NO2rocking vibration appears as a strong vibration at 616 cm-1 in the potassium salt of the ligand 1, while
medium or strong absorptions are observed in the range 614-617 cm-1 in the spectra of derivatives 2-6,
in accordance with an absence of relevant interactions of the NO2 group oxygen atoms in all
derivatives. In the far-IR spectra of derivatives 2-6, we have assigned the broad absorptions from 400
to 550 cm-1 to the phenyl quadrant out of plane bending and in plane bending vibrations, on the basis of
previous reports on free phosphanes and phosphane silver(I) complexes.282
The 1H NMR chemical shifts of 4-CH and 5-CH protons (in CD3OD solution) of the ligand
K[H2B(pzNO2)2], 1, are at  6.74 and  7.62 respectively, close to the values of starting 3-nitropyrazole
( 6.95 and  7.82 in CD3OD). The room temperature 1H NMR spectra of complexes 2-6, in
chloroform solution, show only one set of resonances for H(4) and H(5) protons, in the range 6.68-7.62
ppm, indicating that all the nitropyazole rings are equivalent. The phosphane coligands show a
characteristic series of resonances in the aromatic region. These evidences suggest highly fluxional
species or complete dissociation and reassociation of the pyrazole nitrogens.
In the
31
P NMR spectrum of {[H2B(pzNO2)2]Ag[P(C6H5)3]2}, 2, a single broad signal is observed at
10.25 ppm at 293K and a doublet at 11.53 ppm at 223K, with coupling constants 1J(Ag-31P) at 455 Hz
typical of P2AgN2 species.348 The 1J(Ag–31P) coupling constant values seem to be dependent on the
128
nature of the poly(pyrazol-1-yl)borate donor. For example, 1J(Ag–31P) values observed for derivative 2
and for complexes of general formula {(Bpx)Ag[P(C6H5)3]2}, where Bpx is a bis(azolyl)borato ligand
with electron withdrawing substituents, are always slightly larger than those observed for compounds
where Bpx is [H2B(pz)2] or [H2B(pzMe2)2].260 The coupling constants 1J(Ag–31P), in conjunction with
other physical data, also provide a useful probe for studying changes in molecular structure in solution.
Tentatively, it is possible to analyze, as a first approximation, the correlation between 1J(Ag-P) and
θ(P-Ag-P) in terms of the hybridization model based on the equation given by Pople and Santry.
Structural
and
spectroscopical
data
for
the
related
[H2B(tz)2]Ag[P(C6H5)3]2
and
[H2B(pz)2]Ag[P(C6H5)3]2 are available for comparison.260 These adducts show P-Ag-P angles and
1
J(Ag-P) average values of 127.75° (411 Hz) and 122.51° (387 Hz), respectively, in comparison to
135.15° (455 Hz) values observed for compound [H2B(pzNO2)2]Ag[P(C6H5)3]2 (2). Such a positive
correlation between P-Ag-P angle and solution 1J(Ag-31P) data has been previously observed for other
silver complexes. For a given phosphane, the Ag-P bond length is expected to increase as the P-Ag-P
angle decreases. However, changes in Ag-P distance results in only small changes in 1J(Ag-P).
In the
31
P NMR spectra of derivatives 3-5 a double doublet is observed at 223 K with coupling
constants 1J(107Ag-31P) in the range 653-663 Hz and 1J(109Ag-31P) in the range 742-765 Hz, all typical
of a PAgN2 core.271 In the spectrum of 7, a single broad signal is observed at -7.04 ppm at 293K and a
doublet at -6.90 ppm at 223K, with coupling constant 1J(Ag-31P) at 590 Hz typical of a monophosphane
species.263
Electrospray ionization mass spectroscopy was used to probe the existence of aggregates of the
scorpionate ligand with Ag(I) and phosphane coligand in solution. Both positive-ion and negative-ion
spectra of the ligand 1 and of the complexes 2-6, dissolved in methanol, were recorded at low voltage
(3.5-4.0 kV); under these experimental conditions the dissociation is minimal and most of the analyte is
transported to the mass spectrometer as the intact molecular species. In methanol solution the negativeion spectra of compounds 1-6 were dominated by the fragment at m/z 237 (100%) due to the free
scorpionate ligand, [H2B(pzNO2)2]-. The positive-ion spectra of all the triorganophosphane derivatives
2-6 were dominated by the fragment [Ag(PR3)2]+. These [Ag(PR3)2]+ species could indicate individual
species with a metal to ligand ratio of 1:2 in solution, but given that such stoichiometry has only been
detected for compound 2 they are more likely to arise from solution coordination polymers.289
129
2.2. X-ray crystal structural data
X-ray quality crystals of K[H2B(pzNO2)2] were obtained from a diethyl ether/n-hexane solution. X-ray
crystal structure shows that the bis(pyrazolyl)borate ligand in K[H2B(pzNO2)2] adopts a half-boat
conformation. The nitro groups are essentially coplanar with the pyrazolyl rings. This would facilitate
the maximum electron delocalization between the pyrazolyl ring and the nitro group. In addition to the
intramolecular K-O and K-N(pyrazolyl) bonds as shown in Fig. 42a, the potassium center shows
several intermolecular K-H-B, K-O, and K-arene linkages (Fig. 42b) leading to a overall polymeric
network.
Fig. 42a
Fig. 42b
Fig. 42a. Basic structural unit of K[H2B(pzNO2)2] showing the atom numbering scheme. Fig. 42b. A view of K[H2B(pzNO2)2]
showing the bis(pyrazolyl)borato ligand, and the atoms closest to the potassium center that form inter- and intra-molecular
contacts leading to a polymeric network. Selected bond distances (Å) and angles (°): K-N(5) 2.8144(11), K-N(2)
2.8572(11), K-O(1) 2.9918(10), K-O(3) 3.0235(10), K-O(2)#1 2.7369(10), K-O(1)#2 2.8429(10), K-B#3 3.2621(14), KO(2)#2 3.4192(11), K-C(2)#4 3.5119(13); N(5)-K-N(2) 68.43(3), N(5)-K-O(1) 116.15(3), N(2)-K-O(1) 54.08(3), N(5)-KO(3) 54.32(3), N(2)-K-O(3) 120.03(3), O(1)-K-O(3) 140.50(3), N(4)-B-N(1) 108.15(10); #1, #2 #3 and #4 indicate
symmetry generated atoms.
X-ray crystal structure of [H2B(pzNO2)2]Ag[P(C6H5)3]2 is depicted in Fig. 43. It shows that the
bis(pyrazolyl)borate ligand adopts a half-boat conformation, and the nitro groups are essentially
coplanar with the pyrazolyl rings. The four-coordinate silver center has a pseudo-tetrahedral geometry
with two different Ag-N (2.3970(17), 2.5661(19) Å) and Ag-P (2.4138(6), 2.4641(6) Å) distances. The
P-Ag-P angle is significantly large 135.158(19)°, compared to the typical tetrahedral angles. This is
most likely a steric effect of having two sterically demanding PPh3 groups on the
bis(pyrazolyl)boratosilver unit. Structural data for the related [H2B(tz)2]Ag[P(C6H5)3]2 and
[H2B(pz)2]Ag[P(C6H5)3]2 available.260 These adducts show somewhat similar Ag-P distances but much
smaller P-Ag-P angles compared to [H2B(pzNO2)2]Ag[P(C6H5)3]2.
130
Fig. 43. Molecular structure of [H2B(pzNO2)2]Ag[P(C6H5)3]2. All the hydrogen atoms except those on boron have been
omitted for clarity. Selected bond distances (Å) and angles (°): Ag-N(4) 2.3970(17), Ag-P(2) 2.4138(6), Ag-P(1)
2.4641(6), Ag-N(2) 2.5661(19), N(3)-B 1.566(3), N(6)-O(3) 1.226(2), N(6)-O(4) 1.235(2), N(5)-O(1) 1.235(2), N(5)O(2) 1.235(3), N(1)-B 1.564(3); N(4)-Ag-P(2) 115.40(4), N(4)-Ag-P(1) 98.53(4), P(2)-Ag-P(1) 135.158(19), N(4)-AgN(2) 87.40(6), P(2)-Ag-N(2) 105.02(4), P(1)-Ag-N(2) 104.95(4), N(1)-B-N(3) 110.99(19).
Fig. 44. Molecular structure of [H2B(pzNO2)2]Ag[P(p-C6H4CH3)3]. All the hydrogen atoms except those on boron have been
omitted for clarity. Selected bond distances (Å) and angles (°): Ag-N(4) 2.2481(15), Ag-P 2.3512(4), Ag-N(2) 2.3539(15),
N(1)-B 1.563(3), N(3)-B 1.553(3), N(5)-O(1) 1.225(2), N(5)-O(2) 1.228(2), N(6)-O(3) 1.228(2), N(6)-O(4) 1.233(2), N(4)Ag-P 146.31(4), N(4)-Ag-N(2) 84.70(6), P-Ag-N(2) 124.60(4), N(3)-B-N(1) 108.86(16).
X-ray crystal structure of [H2B(pzNO2)2]Ag[P(p-C6H4CH3)3] is illustrated in Fig. 44. This molecules
features a boat-shaped bis(pyrazolyl)borate ligand and a three-coordinate silver atom. The Ag-N
131
(2.3539(15), 2.2481(15) Å) and Ag-P (2.3512(4) Å) distances are shorter than the corresponding
distance of the four-coordinate [H2B(pzNO2)2]Ag[P(C6H5)3]2 complex.
This is attributable to the reduced steric crowding at the silver center in the three-coordinate molecule.
The silver atom also displays a Ag….H contact (2.82 Å) with the para-methyl group of a neighbouring
P(p-C6H4CH3)3 ligand. This contact appears to be significant enough to distort the silver site slightly
(sum of the angles at silver = 355.6°) from the ideal trigonal planer geometry. X-ray data of the related
three
coordinate
[(pzMe)2B(pzMe)2]Ag[P(p-C6H4CH3)3]271
and
[Ph2B(pz)2]Ag[P(p-C6H4CH3)3]356
available for comparison. They show remarkably similar Ag-P distances. This seems to indicate that
the Ag-P distance is not very sensitive to changes in electronic properties of the pyrazolyl moiety.
3. Summary and conclusion
It is possible to synthesize bis(pyrazolyl)borates bearing electron withdrawing nitro substituents at the
pyrazolyl ring 3-positions. The solid state structure of the potassium salt of [H2B(pzNO2)2]- show
extensive intermolecular contacts leading to a polymeric network. [H2B(pzNO2)2]K is a good ligand
transfer agent. The silver(I) phosphane complexes were synthesized in good yield via a metathesis
process involving [H2B(pzNO2)2]K and AgNO3 in the presence of the appropriate phosphane. The solid
state data show that in silver-phosphane adducts, the bis(pyrazolyl)borate ligand act as a 2-N2 donor.
Nitro groups essentially adopt a coplanar geometry with the pyrazolyl rings. It would facilitate the
maximum electron withdrawing effect of NO2 groups thus making ligands like [H2B(pzNO2)2]- weak
donors. We are currently attempting the synthesis of related tris(pyrazolyl)borates.
132
Chapter 9
Synthesis, Characterization, and in Vitro Antitumor
Properties of Tris(hydroxymethyl)phosphine
Copper(I) Complexes Containing the New Bis(1,2,4triazol-1-yl)acetate Ligand
In this session I report the results obtained in the attempt to study the coordinative ability of the
monoanionic heteroscorpionate acetate ligand, bis(3,5-dimethyl-pyrazol-1-yl)acetate ([HC(CO2)(pzMe2)2]-), toward copper(I) acceptors. Moreover, it has been designed and synthesized the new
triazole-based heteroscorpionate ligand, bis(triazol-1-yl)acetate ([HC(CO2)(tz)2]-); triazole-based
ligands are electron-withdrawing relative to their pyrazole-based counterparts, and the exo-ringnitrogen atoms may bridge between metal centers or may take part in hydrogen-bond interactions,
assisting the formation of two-dimensional water-intercalate or water-layer clathrates,357,358 thus
leading to water soluble species.359-361
Besides, because it is of great importance to obtain complexes that are soluble and stable under
physiological conditions, an interesting solution, as seen in chapters 2 and 3, is the use of watersoluble phosphine coligands bringing highly polar functional groups such as -SO3+, -COOH, -NR3+, or
-OH.349
Following, the synthesis and the spectroscopic and analytic characterization of new triazole-based
scorpionate copper(I) complexes containing the tris(hydroxymethyl)phosphine coligand will be
described.
Furthermore, the in vitro antitumor activity of these new water soluble Cu(I) complexes has been
evaluated, in comparison with cisplatin, which is the most widely used metal-based antitumor drug.362
It is well-known that cisplatin effectiveness is often severely limited by the occurrence of cellular
resistance.344 Thus, one of the main goals in the search for new metal-based anticancer agents is the
circumvention of cisplatin resistance. In this study, the cytotoxicity profile of several copper(I)
complexes containing scorpionate and phosphine ligands against a panel of human tumor cell lines,
133
also including cisplatin-resistant ovarian (C13*) and cervix (A431-Pt) carcinoma cells in which
different molecular mechanisms underlie the resistance, has been investigated.363,364 DNA flow
cytometric analysis and biochemical investigations were performed to study the effects on the cell
cycle and the induction of apoptosis. These investigations were aimed at gaining insight into the
mechanism of action of this new series of copper(I) complexes.
1. Experimental
1.1. Materials and general methods
All syntheses and handling were carried out under an atmosphere of dry oxygen-free dinitrogen, using
standard Schlenk techniques or a glove box. All solvents were dried, degassed, and distilled prior to
use. Elemental analyses (C,H,N,S) were performed in house with a Fisons Instruments 1108 CHNS-O
elemental analyzer. Melting points were taken on an SMP3 Stuart Scientific Instrument. IR spectra
were recorded from 4000 to 100 cm-1 with a Perkin-Elmer System 2000 FTIR instrument. 1H and
31
P
NMR spectra were recorded on a Oxford-400 Varian spectrometer (400.4 MHz for 1H and 162.1 MHz
for 31P). (NMR annotations used: d = doublet, dd = double doublet, dbr = broad doublet, m = multiplet,
m = broad multiplet, s = singlet, sbr = broad singlet, t = triplet). Electrospray mass spectra (ESIMS)
were obtained in positive- or negative-ion mode on a series 1100 MSD detector HP spectrometer. The
compounds were added to the reagent grade water to give solutions of approximate concentration 0.1
mM. These solutions were injected (1 μl) into the spectrometer via a 2 HPLC HP 1090 Series II fitted
with an autosampler. The pump delivered the solutions to the mass spectrometer source at a flow rate
of 300 μl min-1, and nitrogen was employed both as a drying and nebulizing gas. Capillary voltages
were typically 4000 V and 3500 V for the positive- and negativeion mode, respectively. Confirmation
of all major species in this ESIMS study was aided by comparison of the observed and predicted
isotope distribution patterns, the latter calculated using the IsoPro 3.0 computer program.
1.2. Syntheses.
All reagents were purchased from Aldrich and used without further purification. Sodium salt of the
donor Na[HC(CO2)(pzMe2)2]296 and the tris(hydroxymethyl)phosphine coligand were prepared in
accordance with the literature methods.365,366
134
1.3. Na[HC(CO2)(tz)2] (1)
A methanol solution (100 mL) of 1,2,4-triazole (3.000 g, 43.4 mmol) was added to a solution of NaOH
(3.600 g, 90.0 mmol) in 40 mL of absolute ethanol. After 1 day of stirring, a solution of dibromoacetic
acid (4.730 g, 21.7 mmol) in 40 mL of absolute ethanol was added dropwise to the sodium salt so
obtained, and the mixture was stirred for 24 h, allowed to cool to rt, concentrated, and then filtered,
eventually affording a pale yellow solid. The crude product was recrystallized from diethyl
ether/acetone (1:2), yielding Na[HC(CO2)(tz)2] (1) as pale yellow microcrystalline needles; yield 72%;
mp 219-220
C dec. 1H NMR (CD3OD, 293K):  7.28 (s, 1H, CHCOO), 7.98 (s, 2H, 5 CH), 8.84 (s,
2H, 3-CH). IR (nujol, cm-1): 3135w, 3106w (CH), 1661s (asym CO2), 1558m, 1520m (C=C + C=N).
ESIMS (major positive-ions, H2O), m/z (%): 239 (100) {Na[HC(CO2)(tz)2] + Na}+, 455 (60)
{2[HC(CO2)(tz)2] + 3Na}+, 671 (70) {3[HC(CO2)(tz)2] + 4Na}+, 887 (20) {4[HC(CO2)(tz)2] + 5Na}+.
ESIMS (major negative-ions, H2O), m/z (%): 149 (40) {[HC(tz)2]}-, 193 (20) {[HC(CO2)(tz)2]}-, 409
(100) {2[HC(CO2)(tz)2] + Na}-. Calcd for C6H5N6NaO2: C, 33.34; H, 2.33; N, 38.88%. Found: C,
33.09; H, 2.23; N, 39.08%.
1.4. [HC(CO2)(tz)2]Cu[P(CH2OH)3]2 (2)
To a methanol/acetonitrile (1:2) solution (50 mL) of [Cu(CH3CN)4][PF6] (0.373 g, 1.0 mmol) and
P(CH2OH)3 (0.248 g, 2.0 mmol), Na[HC(CO2)(tz)2] (0.216 g, 1.0 mmol) was added at room
temperature. After the addition, the reaction mixture was stirred for 5 h, and solvent was removed
under vacuum. The resulting solid was treated with chloroform (50 mL), and salt was removed by
filtration. The solution was concentrated under vacuum, and a colorless solid was filtered off and
recrystallized from CHCl3/n-hexane (1:5) to give complex 2 in 71% yield; mp 175-176
C. 1H NMR
(D2O, 293K):  3.95 (sbr, 12H, CH2), 5.14 (sbr, 6H, OH), 6.97 (s, 1H, CHCOO), 8.01 (s, 2H, 5-CH),
8.86 (s, 2H, 3-CH). 31P NMR (D2O, 293K):  -10.36 (s). IR (nujol, cm-1): 3302br (OH), 3107m (CH),
1660sbr (asym CO2), 1558w, 1514m (C=C + C=N), 545mbr, 468sbr (R3P), 396w, 334w ( Cu-N).
ESIMS (major positive-ions, H2O), m/z (%): 312 (100) {Cu[P(CH2OH)3]2}+. ESIMS (major negativeions, H2O), m/z (%): 149 (100) {[HC(tz)2]}-, 193 (50) {[HC(CO2)(tz)2]}-. Anal. Calcd for
C12H23CuN6O8P2: C, 28.55; H; 4.59; N, 16.65. Found: C, 28.34; H, 4.47; N, 16.85%.
135
1.5. [HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2 (3)
Complex 3 was prepared analogously to compound 2 by using [Cu(CH3CN)4][PF6] (0.373 g, 1.0
mmol), P(CH2OH)3 (0.248 g, 2.0 mmol), and Na[HC(CO2)(pzMe2)2] (0.270 g, 1.0 mmol). The product
was recrystallized from CHCl3/diethyl ether (1:3) in 65% yield; mp 113-114
C. 1H NMR (D2O,
293K):  2.15 (s, 6H, 3-CH3), 2.29 (s, 6H, 5-CH3), 4.02 (d, 12H, CH2), 5.13 (mbr, 6H, OH), 5.96 (s,
2H, 4-CH), 6.60 (s, 1H, CHCOO). 1H NMR (DMSO, 293K):  2.22 (s, 6H, 3-CH3), 2.36
CH3), 4.15 (d, 12H, CH2), 5.96 (s, 2H, 4- CH), 6.60 (s, 1H, CHCOO).
31
(s, 6H, 5-
P NMR (D2O, 293K):  -
10.28 (sbr). IR (nujol, cm-1): 3370mbr (OH), 3182m (CH), 1647sbr (asym CO2), 1560m (C=C +
C=N), 485mbr, 475mbr, 404m (R3P), 376w (Cu-N). ESIMS (major positive-ions, H2O), m/z (%): 435
(100) {[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3] + H}+, 559 (80) {[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2 +
H}+. ESIMS (major negative-ions, H2O), m/z (%): 247 (100) {[HC(CO2)(pzMe2)2]}-. Anal. Calcd for
C18H33CuN4O8P2: C, 38.68; H; 5.95; N, 10.02. Found: C, 38.89; H, 5.79; N, 10.21%.
1.6. [(CH3CN)2Cu(P(CH2OH)3)2]PF6 (4)
To an acetonitrile solution (40 mL) of [Cu(CH3CN)4][PF6] (0.372 g, 1.0 mmol), a methanol solution
(20 mL) of P(CH2OH)3 (0.249 g, 2.0 mmol) was added at room temperature. After the addition, the
reaction mixture was stirred for 24 h. The resulting white solid was filtered off, washed with
acetonitrile, and recrystallized from acetonitrile/methanol to give complex 5 in 89% yield; mp 124
dec. 1H NMR (D2O, 293K): 
(D2O, 293K): 
1.95 (s, 6H, CH3), 4.05 (s, 12H, CH2), 4.65 (s, 6H, OH).
31
C
P NMR
-11.85 (sbr), -145.14 (septet, J(F–P) = 709.5 Hz, PF6). IR (nujol, cm-1): 3360br (OH),
3134m (CH), 2253m (CN), 560s, 477sbr, 456w (R3P), 397w, 352w, 326w, 279s ( Cu-N). ESIMS
(major positive-ions, CH3OH), m/z (%): 312 (100) {Cu[P(CH2OH)3]2}+. ESIMS (major negative-ions,
CH3OH), m/z (%): 145 (100) {PF6}-, 313 (30) {Na[PF6] + PF6}-, 477 (20) {[Cu(CH3CN)3](PF6)2}-.
Anal. Calcd for C10H24CuF6N2O6P3: C, 22.29; H; 4.49; N, 5.20. Found: C, 22.50; H, 4.40; N, 5.05%.
2. Experiments with human cells
[HC(CO2)(tz)2]Cu[P-(CH2OH)3]2,
2,
[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2,
3,
and
[(CH3CN)2Cu(P(CH2OH)3)2]PF6, 4, complexes and the corresponding uncoordinated ligands were
dissolved in purified water just before the experiment; cisplatin was dissolved in DMSO just before the
experiment and a calculated amount of drug solution was added to the growth medium containing cells
to a final solvent concentration of 0.5%, which had no discernible effect on cell killing. MTT (3-(4,5136
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cisplatin were obtained from Sigma
Chemical Co., St. Louis, MO.
2.1. Cell Cultures
A549, MCF7, and LoVo are human lung, breast, and colon carcinoma cell lines, respectively (ATCC,
Rockville, MD), along with melanoma (A375) and human promyelocytic leukemia (HL60) cell lines;
2008 and its cisplatin resistant variant, C13*, are human ovarian cancer cell line, and they were kindly
provided by Prof. G. Marverti (Dept. of Biomedical Science of Modena University, Italy); A431 and
A431-Pt are sensible and resistant human cervix carcinoma, respectively. They were kindly provided
by Prof. Zunino (Division of Experimental Oncology B, Istituto Nazionale dei Tumori, Milan, Italy).
Cell lines were maintained in the logarithmic phase at 37
C in a 5% carbon dioxide atmosphere, using
the following culture media: (i) RPMI-1640 medium (Euroclone, Celbio, Milan, Italy) containing 10%
fetal calf serum (Biochrom-Seromed GmbH&Co, Berlin, Germany) and supplemented with 25 mM
HEPES buffer, L-glutamine, and the antibiotics penicillin (50 units·mL-1) and streptomycin
(50 g·mL-1) for HL60, MCF7, 2008, C13*, A431, and A431-Pt cells; (ii) F-12 HAM'S (Sigma
Chemical Co.) containing 10% fetal calf serum, L-glutamine, penicillin (50 units·mL-1), and
streptomycin (50
g·mL-1) for LoVo cells; (iii) D-MEM (Dulbecco's modified eagle's medium;
Euroclone) supplemented with 10% fetal calf serum (Euroclone), L-glutamine, penicillin
(50 units·mL-1), and streptomycin (50 g·mL-1) for A549 cells.
2.2. Cytotoxicity assay
The growth inhibitory effect toward tumor cell lines was evaluated by means of MTT (tetrazolium salt
reduction) assay.345 Briefly, 3-8 × 103 cells/well, dependent upon the growth characteristics of the cell
line, were seeded in 96-well microplates in growth medium (100 L) and then incubated at 37
C in a
5% carbon dioxide atmosphere. After 24 h, the medium was removed and replaced with a fresh one
containing the compound to be studied at the appropriate concentration. Triplicate cultures were
established for each treatment. After 48 h, each well was treated with 10 L of a 5 mg·mL-1 MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) saline solution, and after 5 h of
incubation, 100 L of a sodium dodecylsulfate (SDS) solution in 0.01 M HCl was added. After
overnight incubation, the inhibition of cell growth induced by the tested complexes was detected by
measuring the absorbance of each well at 570 nm using a Bio-Rad 680 microplate reader. Mean
absorbance for each drug dose was expressed as a percentage of the control untreated well absorbance
137
and plotted versus drug concentration. IC50 values represent the drug concentrations that reduced the
mean absorbance at 570 nm to 50% of those in the untreated control wells.
2.3. Flow cytometric analysis
Drug-induced cell cycle effects and DNA fragmentation were analyzed by flow cytometry after DNA
staining with propidium iodide (PI) according to Nicoletti et al.367 Briefly, 2008 cells (5 × 105 cells)
were exposed for 1-48 h to tested compound concentrations corresponding to IC50 values. One mL of a
PI solution, containing 50 g/mL of PI, 0.1% m/v of Triton X-100, and 0.01% m/v of sodium citrate,
was added to cells and then incubated for 25 min at 4°C in the dark. Induced cell death was determined
as a percentage of hypodiploid nuclei counted over the total cell population measured by FACSCalibur
flow cytometer (Becton-Dickinson, CA) using a 550-600 nm filter. Analysis was performed by Cell
Quest software (Becton-Dickinson, CA).
2.4. Caspase-3 activity
Caspase-3 activity was detected by using the ApoAlert Caspase-3 Fluorescent Assay Kit (Clontech)
according to the manufacturer-recommended procedures. In the amount of 106, 2008 cells were
collected following 12 or 24 h of incubation of tested compounds (at concentrations corresponding to
IC50 values) and lysed on ice in 50 L of lysis buffer for 10 min and then treated with 50 L of reaction
buffer containing dithiothreitol (DTT) and 5 L of caspase-3 substrate solution (Asp-Glu-Val-Asp-7amino-4-trifluoromethyl-coumarin [DEVD-AFC], Clontech). The fluorescence was determined with a
Perkin-Elmer 550 spectrofluorometer (excitation 440 nm, emission 505 nm). The caspase-3 activity
was expressed as the increase of the AFC-emitted fluorescence. The Student's t-test was used for data
analysis.
3. Results and Discussion
3.1. Syntheses and characterization of Cu(I) complexes
The sodium salt of the bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO2)(tz)2], 1, has been synthesized
by treating a methanol solution of 1,2,4-triazole with a solution of NaOH in 40 mL of absolute ethanol,
followed by a solution of dibromoacetic acid in absolute ethanol (Scheme 25). Compound 1 is an airand moisture-stable pale yellow microcrystalline solid; it is soluble in protic solvents as water,
methanol, and ethanol. The infrared spectra showed weak absorptions near 3100 cm-1 due to the pz ring
138
C-H stretching, and medium to strong absorptions in the range 1520-1560 cm-1 related to ring
"breathing" vibrations. The presence of the carboxylate moiety is detected by two intense, broad
absorptions at 1661 cm-1, due to the asymmetric CO2- stretching mode. The ESI-MS positive-ion
spectrum of 1 in water is dominated by fragments attributable to the aggregation of two (100%), three
(60%), four (70%), and five (20%) sodium ions to the ligand. In the negative-ion spectrum of 1, the
major peak at m/z 409 (100%) is due to the species {2[HC(CO2)(tz)2] + Na}-; other minor peaks are
attributable to the free anionic ligand [HC(CO2)(tz)2]- (20%) and to the decarboxylated species
{[HC(tz)2]}- (40%).
Scheme 25. Synthesis of Sodium Bis(1,2,4-triazol-1-yl)acetate, Na[HC(CO2)(tz)2], 1
Complexes 2 and 3 have been synthesized by reaction of Na[HC(CO2)(tz)2] (1a; Fig. 45) or
Na[HC(CO2)(pzMe2)2] (1b; Fig. 45), with [Cu(CH3CN)4][PF6] and P(CH2OH)3 in methanol/acetonitrile
solutions (eq 1).
Na[L’’] + [Cu(CH3CN)4](PF6) + 2 P(CH2OH)3 →[L’’]Cu[P(CH2OH)3]2
(1)
(2) L1 = [HC(CO2)(tz)2](3) L2 = [HC(CO2)(pzMe2)2]-
Fig. 45. Structure of the ligands employed in this work: (1a) sodium bis(1,2,4-triazol-1-yl)acetate, Na[HC(CO2)(tz)2]; (1b)
sodium bis(3,5-dimethylpyrazol-1-yl)acetate, Na[HC(CO2)(pzMe2)2].
Similar reactions carried out in acetonitrile at room temperature, but without addition of the
heteroscorpionate ligand (eq 2), afforded the bis-solvato complex [(CH3CN)2Cu-(P(CH2OH)3)2]PF6, 4.
Addition of an excess of P(CH2OH)3 did not modify the stoichiometry of the resulting compound.
139
[Cu(CH3CN)4](PF6) + 2 P(CH2OH)3 →{(CH3CN)2Cu[P(CH2OH)3]2}PF6
(2)
Complexes 2-4 are stable in air and soluble in alcohols and water. The identity of these compounds has
been established by ESI-MS, IR, and multinuclear (1H, 31P) NMR spectral studies (Table 8).
Table 8. Relevant IR, 31P NMR, and ESI-MS Data of Copper(I) Complexes 2-4
Comp. IRa (cm-1)
2
3302 br (OH)
31P NMRb
ESI MSc m/z (%)
-10.36 (s)
312 (100) {Cu[P(CH2OH)3]2}+
149 (100) {[HC(tz)2]}-
3107 m (CH)
1660 br s (
3
asym
193 (50) {[HC(CO2)(tz)2]}-
CO2)
3370 br m (OH)
-10.28 (s)
559 (80) {[HC(CO2)(pzMe2)2]- Cu[P(CH2OH)3]2 + H}+
3182 m (CH)
1647 br s (
4
asym
3360 br (OH)
3134 m (CH)
435 (100) {[HC(CO2)(pzMe2)2]- Cu[P(CH2OH)3] + H}+
247 (100) {[HC(CO2)(pzMe2)2]}-
CO2)
-11.85 (br s)
-145.14 (septet, J(F-P) = 709.5
Hz, PF6)
2253 m (CN)
312 (100) {Cu[P(CH2OH)3]2}+
145 (100) {PF6}313 (30) {Na[PF6] + PF6}477 (20) {[Cu(CH3CN)3](PF6)2}-
a
In nujol mull.b In D2O solution at 293 K.c Major positive and negative ions in H2O solution.
The infrared spectra showed all the expected bands for the scorpionate and the phosphane ligands: (i)
weak absorptions in the range 3100-3200 cm-1 due to the pz ring C-H stretching, (ii) medium to strong
absorptions in the range 1550-1560 cm-1 related to ring "breathing" vibrations, (iii) broad peaks in the
range 3300-3370 cm-1 due to the hydroxylic groups of the phosphanes. In derivatives 2 and 3, the
presence of the COO moiety was detected by the appearance of intense absorptions at 1661 and 1647
cm-1. No significant shifts were observed upon complex formation compared to those exhibited by
uncoordinated ligands. In the IR spectrum of complex 4, a medium peak at 2253 cm-1 was assigned to
the stretching vibration of the CN groups.
140
The room-temperature 1H NMR spectra of derivatives 2 and 3, in D2O solution, exhibited only one set
of signals for the triazole rings protons. Upon coordination of the scorpionate ligands with the copper(I)
acceptor, both azole rings and CHCOO protons did not experience large chemical shift variation,
suggesting very weak interaction (or lack of direct bond) of these rings and/or of the carboxylate group
with the metal. In the 31P NMR spectrum of complexes 2-4, only one broad peak is observed at 293 K
in the range of -10.28 to -11.85 ppm (typical of a CuP2 coordination core),348 significantly downfield
shifted if compared to the signal at  -24.7 ppm exhibited by uncoordinated P(CH2OH)3. In the
spectrum of [(CH3CN)2Cu(P(CH2OH)3]2]PF6, 4, the additional septet at -145.14 ppm (JPF = 709.5 Hz)
was assigned to the PF6 counterion.
Electrospray ionization mass spectroscopy was used to probe the existence of aggregates of the
scorpionate ligand with Cu(I) and phosphane coligand in solution. Both positive-ion and negative-ion
spectra of complexes 2-4, dissolved in water, were recorded at low voltage (3.5-4.0 kV); under these
experimental conditions, the dissociation is minimal and most of the analyte is transported to the mass
spectrometer as the intact molecular species. The positive-ion spectrum of compounds 2 and 4 were
dominated by the fragment {Cu[P(CH2OH)3]2}+ at m/z 312 (100%). Instead, in the positive-ion
spectrum of compound 3, the peak due to the protonated species {[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2
+ H}+, together with the peak attributable to the fragment ion {[HC(CO2)(pzMe2)2]Cu[P-(CH2OH)3] +
H}+, generated by the loss of only one tris(hydroxymethyl)phosphane coligand, can be observed. The
negative-ion spectra of compounds 2 and 3 were dominated by the fragments due to the free
scorpionate ligands, together with the decarboxylated species {[HC(tz)2]}- in the case of compound 2.
The spectroscopic and analytical data for the Cu(I) complexes utilized in this study suggest the
tetrahedral molecular structures outlined in Fig. 46.
Fig. 46. Proposed structure of complexes 2-4.
141
3.2. Cytotoxicity studies
[HC(CO2)(tz)2]Cu[P(CH2OH)3]2,
2,
[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2,
3,
and
[(CH3CN)2Cu(P(CH2OH)3)2]PF6, 4, and the corresponding uncoordinated ligands were examined for
their cytotoxic properties against a panel of human tumor cell lines containing examples of lung
(A549), colon (LoVo), and breast (MCF-7) cancer, leukemia (HL60), and melanoma (A375). For
comparison purposes, the cytotoxicity of cisplatin was evaluated under the same experimental
conditions. IC50 values, calculated from the dose-survival curves obtained after 48 h of drug treatment
from the MTT test, are shown in Table 9.
Table 9. Cytotoxic Activitya
IC50 ( M) ± S.D.
Comp.
HL60
A549
[HC(CO2)(tz)2]Cu[P(CH2OH)3]2, 2
34.31 ± 3.9 25.13 ± 1.1 11.29 ± 1.7 26.66 ± 2.0 32.28 ± 3.6
[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2, 3
10.60 ± 2.5 2.10 ± 1.3 1.55 ± 0.19 2.55 ± 0.9 7.83 ± 1.3
[(CH3CN)2Cu(P(CH2OH)3]2]PF6, 4
21.15 ± 2.8 14.81 ± 0.9 16.7 ± 2.7 21.52 ± 1.7 47.17 ± 2.9
Na[HC(CO2)(tz)2], 1a
ND
P(CH2OH)3
58.67 ± 2.3 72.97 ± 2.4 64.21 ± 4.2 88.71 ± 3.8 65.21 ± 3.2
Na[HC(CO2)(pzMe2)2], 1b
ND
cisplatin
19.9 ± 2.5 39.27 ± 1.9 30.18 ± 1.5 20.28 ± 1.3 24.97 ± 1.5
ND
ND
MCF-7
ND
A375
ND
88.81 ± 3.9 ND
LoVo
ND
ND
a
ND = not detectable. S.D. = standard deviation. IC50 values were calculated by probit analysis (P < 0.05, 2 test). Cells (58 × 104·mL-1) were treated for 48 h with increasing concentrations of tested compounds. Cytotoxicity was assessed by MTT
test.
Uncoordinated ligands proved to be quite ineffective in all tumor cell lines; P(CH2OH)3 gave detectable
IC50 values that were, anyway, markedly higher than those of the corresponding copper(I) complexes.
Compounds 2 and 4 showed IC50 values comparable with those exhibited by cisplatin against HL60,
A375, and LoVo cell lines, whereas their cytotoxic activity was significantly higher against A549 and
MCF-7 cell lines. This general behavior is magnified in the case of complex 3, whose cytotoxic
potency exceeded that of the parent drug by a factor ranging from about 2 to 15. The encouraging
results obtained against the in-house panel of cell lines prompted me and my research group to test the
cytotoxic activity of our Cu(I) complexes onto two additional cell line pairs, which were selected for
their resistance to cisplatin, 2008/C13* ovarian cancer cells, and A431/A431-Pt cervix carcinoma cells.
142
Although cisplatin resistance is multifactorial, the main molecular mechanisms involved in resistance
in these sublines have almost been defined. In C13* cells, resistance is correlated to reduced cellular
drug uptake, high cellular glutathione levels, and enhanced repair of DNA damage. 43 In human
squamous cervix carcinoma A431-Pt cells, resistance is due to defect in drug uptake and to decreased
levels of proteins involved in DNA mismatch repair (MSH2), causing an increased tolerance to
cisplatin-induced DNA damage. Cytotoxicity of tested compounds in sensitive and resistant cells was
assessed after a 48-h drug exposure by the MTT test (Table 10). Cross-resistance profiles were
evaluated by means of the resistance factor (RF), which is defined as the ratio between IC 50 values
calculated for the resistant cells and those arising from the sensitive ones. Remarkably, all the tested
copper(I) complexes exhibited a different cross-resistance profile than that of cisplatin. Against the
ovarian cancer, RF values were about 6 to 18 times lower than those calculated for cisplatin, while
against the cervix cell line pair, they were 3 to 5 times lower.
Table 10. Cross-Resistance Profilesa
Compound
2008 IC50 ( M) C13* IC50 ( M)
R.F.
[HC(CO2)(tz)2]Cu[P(CH2OH)3]2, 2
26.36 ± 1.9
12.40 ± 2.2
0.47
[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2, 3 6.6 ± 1.1
8.16 ± 2.5
1.23
[(CH3CN)2Cu(P(CH2OH)3]2]PF6, 4
24.04 ± 1.8
19.12 ± 1.9
0.79
cisplatin
12.69 ± 1.7
89.18 ± 4.5
7.02
Compound
A431 IC50 ( M) A431/Pt IC50 ( M) R.F.
[HC(CO2)(tz)2]Cu[P(CH2OH)3]2, 2
49.27 ± 2.3
32.44 ± 2.0
0.65
[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2, 3 7.04 ± 0.9
5.72 ± 2.1
0.81
[(CH3CN)2Cu(P(CH2OH)3]2]PF6, 4
43.63 ± 1.4
23.09 ± 1.9
0.52
cisplatin
22.0 ± 1.0
57.76 ± 1.8
2.62
a
S.D. = standard deviation. IC50 values were calculated by probit analysis (P < 0.05, 2 test). Cells (3-5 × 104·mL-1) were
treated for 48 h with increasing concentrations of tested compounds. Cytotoxicity was assessed by MTT test. Resistant
factor (R.F.) is defined as IC50 resistant/parent line.
The overcoming of cross-resistant phenomena in both cell line pairs strongly supports the hypothesis of
a different pathway of action of these copper(I) complexes from that of cisplatin. Also, in this set of
experiments, complex 3 appeared to be the most effective derivative, giving IC50 values 2-3 times
lower than the reference drug on the parental sensitive cell lines and 10 times lower on the cisplatin143
resistant ones. The lower cytotoxicity displayed by complexes 2 and 4 might be related to their
moderate stability (see mass spectrometric and IR and NMR spectroscopic data), which likely arises
from partial in vitro hydrolysis of these species, thus diminishing their availability for cellular uptake
and intracellular trafficking.
3.3. Cell cycle and apoptosis studies
It has been consequently studied further the cellular effects induced by the representative complex 3 in
terms of cell cycle modifications and induction of apoptosis, aiming at the understanding of a possible
mechanism of action. Up to now, there are very few mechanistic studies dealing with the anticancer
activity of copper(I) compounds. Cu(I) complexes of the type [Cu(dppey)]Cl (where dppey denotes cisPh2PCH=CHPPh2) have been supposed to act on mitochondria by uncoupling the oxidative
phosphorylation by inner mitochondrial membrane depolarization.338 More recently, the potent
cytotoxic activity promoted by [Cu2(DPPE)3-(CH3CN)2](ClO4)2 (DPPE = Ph2PCH2-CH2PPh2) against
human lung cancer cells was found to be due to a p53-mediated cell cycle arrest and apoptosis.368
Table 11. Cell Cycle Phasesa
18 h
ctrl
24 h
3
P values ctrl
48 h
3
P values ctrl
3
P values
SUB-G1% 3.34 ± 0.89 3.21 ± 1.20 >0.05
2.31 ± 0.22 10.43 ± 1.90 0.03
2.44 ± 0.17 9.29 ± 0.46 <0.001
G1%
63.88 ± 0.57 50.02 ± 0.99 <0.001
46.28 ± 0.11 28.25 ± 1.33 0.003
59.51 ± 1.39 24.32 ± 1.55 <0.001
G2/M%
33.23 ± 0.95 48.26 ± 0.54 <0.001
52.27 ± 0.14 62.43 ± 0.55 0.002
38.65 ± 1.24 67.09 ± 1.66 <0.001
a
Percentage of cells in different cell cycle phases as a function of time exposure to IC 50 concentrations of complex 3 vs
control cells (P values were determined by the Welch t-test).
To explore complex 3 mode of action on induced cell death, a time-dependent evaluation of the cellcycle profile of 2008 human ovarian carcinoma cells treated with complex 3 by fluorescence-activated
cell sorting has been performed (Fig. 47). Cisplatin was used under the same experimental conditions
as positive control. Treatment of cells with IC50 concentrations of complex 3 resulted in a timedependent increase of G2/M subpopulation within 1-48 h (Fig. 47, panels A-C). In particular, after 48 h
treatment, the percent of cells in the G2/M phase was significantly higher (about 30%) than that of
control cells (Table 11). However, a reduction of G1 cells fraction was observed even at 18 h
144
incubation (Fig. 3, panel A). On the contrary, the percentage of 2008 cells with hypodiploid DNA
markedly increased by treatment with cisplatin; in particular, the percentage of cells with fragmented
DNA was higher (27%) compared to the control samples (Table 11). These results, pointing out a
scarce presence of classical signs of apoptosis, suggest that complex 3-treated cells mainly died
through a nonapoptotic cell death mechanism.
Fig. 47. Cell cycle analysis of 2008 human ovarian cancer cells. Panels A-C represent different time points (18, 24, and 48
h, respectively) of control cells (left) and cells treated with IC 50 concentrations of complex 3 (right). Panel D represents
control cells after 18 h in normal medium (left) and cells treated with IC 50 concentrations of cisplatin (right).
Caspase-3 is a well-known executor enzyme in apoptosis,369 and cisplatin may cause apoptosis
associated with increased caspase-3 activity.370 Complex 3 was tested for its ability to induce caspase-3
activation in lysates of 2008 cells over a period of 24 h (Fig. 48). Treatment with IC50 concentrations of
complex 3 did not result in a significant enhancement of enzyme activity with comparison to untreated
cells at any incubation time tested. In contrast, in cisplatin-treated cells, caspase-3 activity became
145
significantly higher than that detected in control cells already at 12 h, being about 6 times the control
value.
Fig. 48. Induction of caspase-3. The 2008 cells were incubated with IC50 concentrations of complex 3 or cisplatin and then
submitted to the test on caspase-3 induction as described in Experimental Section. Data are the means of at least three
independent experiments. Error bars indicate standard deviation. *P < 0.01 compared to untreated cells.
An additional insight into the cytotoxic potential of the new copper(I) complex has been offered by
forward and side light scatter that are used as indices of cell size and cell granularity, respectively.
After exposure to IC50 concentrations of complex 3, 2008 cells showed a marked increase of cell size
and of cell granularity (Fig. 49, upper right quadrant); these alterations became extremely pronounced
after a 48 h treatment (Fig. 49, panel C). These remarkable morphological changes may be related to
the ability of complex 3 to cause an extensive cytosolic vacuolization. Actually, it is well-known that
cells with increased light scattering properties may contain structures such as vacuoles or aggregated
proteins. Taken together, all these data appear to be in agreement with the hypothesis that the new
copper(I) complex may activate a cell death pathway distinct from apoptosis, namely, paraptosis. This
alternative programmed cell death has been recently characterized by cytoplasmatic vacuolation and,
typically, does not involve activation of caspases, the formation of apoptotic bodies, or other
characteristics of apoptosis. A similar parapoptotic cell death mechanism has been recently described in
human fibrosarcoma cells treated with a Cu(II) thioxotriazole complex, which caused many
146
cytoplasmic vesicles that progressively enlarged and coalesced until the late phases of the cell death
process.371
Fig. 49. Forward scattering vs side scattering as a function of time in 2008 cells untreated (left) and treated with IC 50
concentrations of complex 3 (right)
The delineation of a cell-death mechanism different from that elicited by cisplatin makes this watersoluble copper(I) complex 3 a very interesting candidate for the development of new metal-based drugs
with improved pharmacokinetic properties that is able to overcome the intrinsic or acquired resistance
of several tumors to platinum drugs.
147
Chapter 10
New triorganotin(IV) complexes of a polyfunctional
S,N,O-ligand
In recent years many organotin compounds have been tested for their in vitro activity against a large
variety of tumor lines and have been found to be as effective or better than traditional heavy metal
anticancer drugs such as cis-platin.372,373 In addition to the aforesaid applications organotin compounds
are also of interest in view of the considerable structural diversity they possess. This aspect has been
attracting the attention of a number of researchers and a multitude of structural types have been
discovered.374-377
Recently, it has been reported the synthesis and the spectroscopic characterization of new
poly(pyrazolyl)borate295,378 and poly(imidazolyl)borate379-381 complexes containing organotin(IV)
acceptors. It has been my endeavor to develop the chemistry of organotin compounds bearing coligands of ambidentate character. The primary impetus has been to comprehend competitive
coordination modes of poly(azolyl)borate ligands to the tin atom and find a rationale related to the
stability and structural motifs of this class of compounds.276
As an extension of this research field, the interest is now focussed on the development of the chemistry
of some new organotin carboxylates obtained by the interaction of a number of organotin(IV) halides
with new polyfunctional S,N,O-ligands, containing two pyridine groups and other biologically relevant
hydrophilic moieties, such as carboxylate groups.
Many series of diorganotin carboxylates have been synthesized, either for investigating their structural
chemistry,377,382-384 or for assessing their performance as PVC stabilizers, biocides, metal-based drugs
and,372,373 anion-recognition agents and catalysts for polyurethane foams,385 for room temperature
vulcanisation of silicon rubbers, for transesterifications,386 for acetylations of alcohols387 and for
dehydrations of alcohols to ethers.388 The diverse structural motifs known in this family of compounds
are primarily attributed to the ambidentate character of the carboxylate ligands and also the tendency of
148
the tin atom to expand its coordination sphere from four to seven. Steric and electronic attributes of
organic substituents on tin and/or the carboxylate moiety impart significant influence on the structural
characteristics of tin carboxylates. Recently, a number of carboxylate ligands bearing additional
strategically placed functional group(s)/donor atom(s) capable of multidentate coordination have been
used to derive a structurally interesting class of tin compounds.389-394
In recent years a number of authors395-404 have synthesized S,N-ligands of the type (CH2)n(SAz)2
(Scheme 26) based on a nitrogenated aromatic ring system such as benzimidazole (Scheme 26(a)) or
pyridine (Scheme 26(b)). These ligands are able to coordinate by both S and the neighbouring N atom,
and hence to form stable chelate rings of five or more atoms.405-412
Scheme 26
Bearing in mind the above, in my research group, I have developed a strategy for producing a new class
of monoanionic and polyfunctional N,O,S-ligands of considerable co-ordinative flexibility. Toward this
end, I report now the synthesis and characterization of some new complexes obtained from the
interaction of a number of triorganotin(IV) halides with the novel sodium bis(2-pyridylthio)acetate
ligand (Scheme 26(d)).
Crystallisation of the compound {[(pyS)2CHCO2]Sn(CH3)3}n (2), from chloroform/diethyl ether
solution, yields the complex {[(pyS)2CHCO2]Sn(CH3)3}n · CHCl3, which has been characterized by Xray crystallography.
1. Experimental
1.1. General
All reagents were purchased from Aldrich (Milwaukee) and used as received. All syntheses were
carried out under a nitrogen atmosphere. All solvents were distilled and degassed with dry nitrogen
prior to use. The samples for microanalysis were dried in vacuo to constant weight (20 C, ca. 0.1 Torr).
Elemental analyses (C, H, N, S) were performed with a Fisons Instruments 1108 CHNS-O Elemental
149
analyser. IR spectra were recorded from 4000 to 100 cm−1 with a Perkin–Elmer System 2000 FT-IR
instrument. 1H and
119
Sn NMR spectra were recorded on a VXR-300 Varian instrument operating at
room temperature (respectively at 300 MHz for 1H, 75 MHz for 13C and 111.9 MHz for 119Sn). Melting
points were taken on an SMP3 Stuart Scientific Instrument. The electrical conductivity measurements
(Λm, reported as Ω−1 cm2 mol−1) of acetone or dichloromethane solutions were taken with a Crison
CDTM 522 conductimeter at room temperature. Electrospray mass spectra (ESIMS) were obtained in
positive- or negative-ion mode on a Series 1100 MSD detector HP spectrometer, using an acetone
mobile phase. The compounds were added to the reagent grade acetone to give solutions of
approximate concentration 0.1 mM. These solutions were injected (1 μl) into the spectrometer via a
HPLC HP 1090 Series II fitted with an autosampler. The pump delivered the solutions to the mass
spectrometer source at a flow rate of 300 μl min−1, and nitrogen was employed both as a drying and
nebulizing gas. Capillary voltages were typically 4000 and 3500 V for the positive- and negative-ion
mode, respectively. Confirmation of all major species in this ESIMS study was aided by comparison of
the observed and predicted isotope distribution patterns, the latter calculated using the IsoPro computer
program.
1.2. Synthesis of [(pyS)2CHCO2]Na (1)
2-Mercaptopyridine (5.508 g, 50.0 mmol) was added to a solution of NaOH (3.600 g, 90.0 mmol) in
40 ml of absolute ethanol. After 1 day stirring, a solution of dichloroacetic acid (3.198 g, 25.0 mmol) in
40 ml of absolute ethanol was added drop wise to the sodium salt so obtained, and this mixture was
stirred for 4 days and then heated at gentle reflux for 12 h to give a pale yellow emulsion. The mixture
was allowed to cool to r.t. and concentrated and then filtered affording a pale yellow solid. The crude
product was recrystallized in ethanol/acetone (1:1) yielding Na[(pyS)2CHCO2] (1) as pale yellow
microcrystalline needles. Yield: 76%, m.p. 213–215 C. 1H NMR (D2O, 293 K): δ 5.78 (s, 1H, CHCO2),
7.20 (m, 2H, 5-CH), 7.44 (m, 2H, 3-CH), 7.67 (m, 2H, 4-CH), 8.30 (m, 2H, 6-CH). 1H NMR (CD3OD,
293 K): δ 6.08 (s, 1H, CHCO2), 7.08 (m, 2H, 5-CH), 7.45 (m, 2H, 3-CH), 7.62 (m, 2H, 4-CH), 8.33 (m,
2H, 6-CH). 1H NMR (CDCl3, 293 K): δ 5.60 (s, 1H, CHCO2), 7.10 (m, 2H, 5-CH), 7.50 (m, 2H, 3CH), 7.65 (m, 2H, 4-CH), 8.36 (m, 2H, 6-CH). 13C NMR (CD3OD, 293 K): δ 5.44 (CHCO2), 121.48
(5-CH), 123.93 (3-CH), 138.18 (4-CH), 150.28 (6-CH), 160.40 (2-CH). IR (nujol, cm−1): 3046w (CH),
1615s (νasym C
O), 1581m, 1555m (C
C+C
N), 1411m (νsym C
O), 1376m, 1132m, 745m.
ESIMS (major positive-ions, CH3OH), m/z (%): 301 (100) [{(pyS)2CHCO2H} + Na+]+, 579 (80)
[{(pyS)2CHCO2H}2 + Na+]+. ESIMS (major negative-ions, CH3OH), m/z (%): 110 (100) [(pyS)]−, 233
150
(30) [{(pyS)2CHCO2} − CO2]−, 577 (30) [{(pyS)2CHCO2}2 + Na+]−. Anal. Calc. for C12H9N2NaO2S2:
C, 47.99; H, 3.02; N, 9.33; S, 21.35. Found: C, 48.02; H, 3.08; N, 9.03, S, 21.40%.
1.3. {[(pyS)2CHCO2]Sn(CH3)3}n (2)
To a CH2Cl2 solution (50 ml) of Me3SnCl (0.199 g, 1.0 mmol), Na[(pyS)2CHCO2] (0.300 g, 1.0 mmol)
was added. The mixture reaction was stirred for 12 h at room temperature, then solvent was removed
on a rotary evaporator and chloroform was added (20 ml). The NaCl was removed by filtration and the
filtrate reduced to half volume. Then diethyl ether was added (40 ml) and a yellow precipitate afforded,
which was filtered off, washed with n-hexane (10 ml) and dried to constant weight under reduced
pressure. Yield: 58%, m.p. 138–140 C. 1H NMR (CDCl3, 293 K): δ 0.53 (s, 9H, Sn–CH3, 2J(Sn–
1
H) = 57.3 Hz), 6.55 (s, 1H, CHCO2), 7.00 (m, 2H, 5-CH), 7.24 (m, 2H, 3-CH), 7.51 (m, 2H, 4-CH),
8.43 (m, 2H, 6-CH).
Sn-CH3, 1J(119Sn,
Sn NMR (CDCl3, 293 K): δ 149.2 (s).
119
13
C NMR (CDCl3, 293 K): δ −1.98 (s,
13
C) = 410 Hz), 48.89 (CHCO2), 120.20 (5-CH), 122.50 (3-CH), 136.34 (4-CH),
149.55 (6-CH), 157.42 (2-CH). IR (nujol, cm−1): 3190w, 3058w (CH), 1616s (νasym C
1558s (C
C+C
N), 1413m (νsym C
O), 1574s,
O), 550sbr (Sn–C), 509s, 485sh (Sn–O). ESIMS (major
positive-ions, CH3OH), m/z (%): 164 (20) [(CH3)3Sn]+, 442 (100) [(CH3)3Sn{(pyS)2CHCO2H}]+, 905
(70) [{(CH3)3Sn}2{(pyS)2CHCO2}2 + Na+]+. ESIMS (major negative-ions, CH3OH), m/z (%): 110
(100) [(pyS)]−, 233 (40) [{(pyS)2CHCO2} − CO2]−, 718 (20) [(CH3)3Sn{(pyS)2CHCO2}2]−. Anal. Calc.
for C15H18N2O2S2Sn: C, 40.73; H, 4.10; N, 6.34; S, 14.47. Found: C, 40.35; H, 4.20; N, 6.08; S,
14.08%.
1.4. {[(pyS)2CHCO2]Sn(C4H9)3} (3)
Compound 3 was prepared similarly to compound 2, stirring (C4H9)3SnCl (0.326 g, 1.0 mmol) and
Na[(pyS)2CHCO2] (0.300 g, 1.0 mmol) in dichloromethane solution (30 ml). Re-crystallization from
petroleum ether gave complex 3 as a micro-crystalline solid (55% yield), m.p. 66–68 C. 1H NMR
(CDCl3, 293 K): δ 0.83 (t, 9H, CH3 of Sn–Bun), 1.15–1.35 (m, 12H, CH2 of Sn–Bun), 1.45–1.65 (m,
6H, CH2 of Sn–Bun), 6.50 (s, 1H, CHCO2), 6.97 (m, 2H, 5-CH), 7.23 (m, 2H, 3-CH), 7.46 (m, 2H, 4CH), 8.40 (m, 2H, 6-CH).
(CH), 1614m (νasym C
119
Sn NMR (CDCl3, 293 K): δ 130.3 (s). IR (nujol, cm−1): 3176w, 3095w
O), 1577m, 1557m (C
C+C
N), 1415m (νsym C
O), 619br, 603sbr (Sn–
C), 506sbr, 481sh (Sn–O). ESIMS (major positive-ions, CH3OH), m/z (%): 290 (60) [(C4H9)3Sn]+, 323
(30)
[{(pyS)2CHCO2} + 2Na+]+,
568
(80)
[(C4H9)3Sn{(pyS)2CHCO2H}]+,
590 (60) [{(C4H9)3Sn}{(pyS)2CHCO2} + Na+]+, 1158 (100) [{(C4H9)3Sn}2{(pyS)2CHCO2}2 + Na+]+.
151
ESIMS (major negative-ions, CH3OH), m/z (%): 110 (40) [(pyS)]−, 233 (20) [{(pyS)2CHCO2} − CO2]−,
845 (100) [(C4H9)3Sn{(pyS)2CHCO2}2]−. Anal. Calc. for C24H36N2O2S2Sn: C, 50.81; H, 6.40; N, 4.94;
S, 11.30. Found: C, 50.75; H, 6.72; N, 4.83; S, 11.22%.
1.5. {[(pyS)2CHCO2]Sn(C6H11)3} (4)
Compound 4 was prepared similarly to compound 2, by using (C6H11)3SnCl (0.404 g, 1.0 mmol) and
Na[(pyS)2CHCO2] (0.300 g, 1.0 mmol) in dichloromethane solution (30 ml). Re-crystallization from
petroleum ether gave complex 4 as a micro-crystalline solid (60% yield), m.p. 104–106 C. 1H NMR
(CDCl3, 293 K): δ 1.06–1.94 (m, 33H, C6H11), 6.47 (s, 1H, CHCO2), 6.97 (m, 2H, 5-CH), 7.26 (m, 2H,
3-CH), 7.47 (m, 2H, 4-CH), 8.40 (m, 2H, 6-CH).
cm−1): 3137w, 3038w (CH), 1651m (νasym C
119
Sn NMR (CDCl3, 293 K): δ 73.2 (s). IR (nujol,
O), 1574m, 1557m (C
C+C
N), 1414m (νsym C
O), 552sbr (Sn–C), 491sbr, 483sh (Sn–O). ESIMS (major positive-ions, CH3OH), m/z (%): 279 (100)
[{(pyS)2CHCO2H} + H+]+, 647 (40) [{(C6H11)3Sn}{(pyS)2CHCO2H}]+. ESIMS (major negative-ions,
CH3OH),
m/z
(%):
110
(100)
[(pyS)]−,
233
(20)
[{(pyS)2CHCO2} − CO2]−,
923
(30)
[(C6H11)3Sn{(pyS)2CHCO2}2]−. Anal. Calc. for C30H42N2O2S2Sn: C, 55.82; H, 6.56; N, 4.34; S, 9.93.
Found: C, 55.35; H, 6.92; N, 4.03; S, 9.30%.
1.6. {[(pyS)2CHCO2]Sn(C6H5)3} (5)
Compound 5 was prepared similarly to compound 2, by using (C6H5)3SnCl (0.386 g, 1.0 mmol) and
Na[(pyS)2CHCO2] (0.300 g, 1.0 mmol) in dichloromethane solution (30 ml). Re-crystallization from
petroleum ether gave complex 5 as a micro-crystalline solid (72% yield), m.p. 108–110 C. 1H NMR
(CDCl3, 293 K): δ 6.55 (s, 1H, CHCO2), 6.89 (m, 2H, 5-CH), 7.17 (m, 2H, 3-CH), 7.38–7.85 (m, 17H,
C6H5 and 4-CH), 8.15 (m, 2H, 6-CH).
3150w (CH), 1656s (νasym C
119
Sn NMR (CDCl3, 293 K): δ −100.2 (s). IR (nujol, cm−1):
O), 1580m, 1557m (C
C+C
N), 1414m (νsym C
O), 482mb (Sn–
O), 274s (Sn–C). ESIMS (major positive-ions, CH3OH), m/z (%): 383 (80) [(C6H5)2Sn(pyS)]+, 628 (80)
[(C6H5)3Sn{(pyS)2CHCO2H}]+,
717
(100)
[{(C6H5)3Sn}O{(C6H5)3Sn} + H+]+,
977
(30)
[{(C6H5)3Sn}2{(pyS)2CHCO2}]+, 1278 (60) [{(C6H5)3Sn}2{(pyS)2CHCO2}2 + Na+]+. ESIMS (major
negative-ions, CH3OH), m/z (%): 110 (100) [(pyS)]−, 233 (40) [{(pyS)2CHCO2} − CO2]−, 627 (10)
[{(C6H5)3Sn}{(pyS)2CHCO2} − H+]−, 905 (60) [{(C6H5)3Sn}{(pyS)2CHCO2}2]−. Anal. Calc. for
C30H24N2O2S2Sn: C, 57.44; H, 3.86; N, 4.47; S, 10.22. Found: C, 57.13; H, 4.00; N, 4.07; S, 10.08%.
152
1.7. X-ray crystallography
The crude complex 2 was dissolved in chloroform/diethyl ether solution; a single crystal of
{[(pyS)2CHCO2]Sn(CH3)3}n · CHCl3 suitable for X-ray diffraction analysis was obtained and mounted
on a Rigaku AFC5R diffractometer using graphite-monochromatized Cu Kα radiation (1.54178 Å) and
a rotating anode
generator. The crystals
are triclinic,
a = 10.132(5) Å,
b = 13.845(3) Å,
c = 14.783(3) Å, α = 84.39(2), β = 77.90(2), γ = 88.15(3), V = 2018(1) A3, T = 293 K, space group
(no. 2), Z = 2, μ(Cu Kα) = 14.2 mm−1, 6676 reflections measured, 6375 unique (Rint = 0:053), 3489
observed (I > 3σ(I)) were used in all calculations. The cell parameters were refined by least squares
from the angular positions of 14 reflections in the range 68.77 < 2θ < 63.98. The data were measured at
room temperature for 6.1 < 2θ < 124.5 using a θ/2θ scan technique. The data were processed to yield
values of I and σ(I) corrected for Lorentz, polarisation and absorption effects. The psi scans used for
the last correction present severe values (about 15%) of the transmission coefficients. The observed
reflections were processed by the direct methods program SIR2004,352 which provided the complete
structure. The successive fourier maps showed the presence of a molecule of chloroform. All nonhydrogen atoms were refined by full-matrix least squares method with anisotropic thermal parameters.
The hydrogen atoms were idealised (C–H = 0.96 Å). Each H atom was assigned the equivalent
isotropic temperature factor of the parent atom multiplied for 1.3 and allowed to ride on it. At the end
of the refinement, a further semi empirical absorption correction was made on the basis of the method
of Walker and Stuart, using the program written by Ugozzoli413 and then the structure converged at the
final R(F) and wR(F2) of 0.056 and 0.074, respectively. The final difference Fourier map with a rootmean-square deviation of electron density of 0.2 e Å−3 showed no significant features. Calculations
were performed using the SIR2004 structure determination package Crystallographic data have been
deposited at the CCDC and allocated the deposition number CCDC 264907.
2. Results and discussion
Complexes 2–5 have been synthesized by methathetic reaction of Na[(pyS)2CHCO2] (1) (Scheme
26(d)) with SnR3Cl acceptors in CH2Cl2 solution (Eq. (1)).
(1)
153
The derivatives 2–5 are stable in air. The complexes are stable in alcohols, acetone, acetonitrile and
chlorinated solvents, and they are non-electrolytes in CH2Cl2 solution. The identity of these compounds
has been established by ESI-MS, IR and multinuclear (1H and 119Sn) NMR spectral studies.
The infrared spectra carried out on the solid samples (nujol mull) showed all the expected bands for the
ligand and the tin moieties: weak absorptions near 3100 cm−1 are due to the pyridine rings C–H
stretching and medium to strong absorptions in the range 1550–1580 cm−1 are related to ring
“breathing” vibrations.
The presence of the COO moiety is detected by intense absorptions in the range 1614–1656 cm−1 and
1413–1415 cm−1 due to the asymmetric and symmetric CO2− stretching mode, respectively, not
significantly shifted with respect to the free ligand (νasym CO2− = 1615 cm−1, νsym CO2− = 1411 cm−1).
In the far-IR region medium to strong absorptions appear upon coordination, due to the stretching
modes of Sn–N and Sn–R. The absence of Sn–Cl stretching vibrations in the spectra of 2–5 confirms
the substitution of the chloride in the complexes formation. In the far-IR spectra the Sn–C stretching
frequencies fall as strong or medium broad bands in the range 550–619 cm−1 for alkyl derivatives 2–4,
and at 274 cm−1 for tri(phenyl) complex 5; these absorptions well agree with the trends previously
observed in similar N-donor complexes.414 In the far-IR spectra of 2–5 absorptions assigned to Sn–O
have been always detected between 481 and 509 cm−1.
The room temperature 1H NMR spectra of derivatives 2–5, in CDCl3 solution (see Section 2), exhibit
only one set of signals for the protons of the pyridyl rings of the [(pyS)2CHCO2]− ligand.
Upon interaction of ligand 1 with organotin(IV) acceptors, for all complexes studied, no significantly
large shifts were evident for the proton atoms of pyridyl rings: this implies a lack of direct bond
involvement of these rings with the metal. In contrast, in the 1H NMR spectra of complexes 2–5 the
signals due to the CHCOO group exhibit significant downfield shift (from 6.08 ppm in the free ligand
to 6.47–6.55 ppm in the complexes): this is suggestive of a strong bonding of the tin atom to the
carboxylate group of complexes.
The tin-hydrogen, 2J(119Sn,1H), and tin-carbon, 1J(119Sn,13C), coupling constants in various cases can be
correlated with the percentage of s-character which the Sn atom presents in the Sn–C bond and hence
2
J(119Sn,1H) and 1J(119Sn,13C) may give information about the coordination number of tin. In the
tri(methyl)tin(IV) derivative 2 the tin-proton coupling constant 2J(119Sn,1H) is 57.3 Hz, falling in the
range of four-coordinated trimethyltin(IV) species. The tin-carbon coupling constant of compound 2,
1
J(119Sn,13C), is 410 Hz; on the basis of Lockarts’s equation, the Me–Sn–Me angle is estimated to 111,
suggesting a distorted tetrahedral disposition of Me groups.
154
The
119
Sn chemical shifts of triorganotin(IV) derivatives 2–5, at 149.2, 130.3, 73.2 and −100.2 ppm,
respectively, are in accordance with those of four-coordinated triorganotin(IV) complexes involving S-,
O- or N-donors.415
Electrospray ionization is considered a ‘soft’ ionization technique and is particularly suitable for study
of labile organotin systems in solution. ESI mass spectra, dissolved in methanol solution and detected
at fragmentation voltage of 30 V, show molecular ion peaks and structurally important fragment ions.
For the ligand 1 significant fragments at m/z 301 and 579 in the positive- and at m/z 577 in the
negative-ion spectra have been attributable to aggregates of the ligand with Na+; peaks at m/z 110 and
233, respectively, due to the fragments [(pyS)]− and [{(pyS)2CHCO2} − CO2]−, are present in the
negative-ion spectrum of 1. Peaks at m/z 110, 233, 279 and 323, due to the free O-donor ligand or its
decomposition fragments, are also present in the spectra of all derivatives 2–5.
Peaks due to the free organotin(IV) acceptors [R3Sn]+ are present in the cationic spectra of derivatives
2 and 3, due to the instability of these triorganotin derivatives. The instability of triorganotin(IV)
derivatives in methanol solutions is also demonstrated by the presence in the positive-ion spectrum of
the triphenyl derivative 5 of a fragment at m/z 383, due to the aggregate [(C6H5)2Sn(pyS)]+. In the
electrospray spectra of all the triorganotin derivatives 2–5, peaks due to species containing the
triorganotin fragments associated to one or two molecules of the ligand have been detected.
Crystallisation of the compound {[(pyS)2CHCO2]Sn(CH3)3}n (2), from chloroform/diethyl ether
solution, yields the chloroform complex {[(pyS)2CHCO2]Sn(CH3)3}n · CHCl3. The identity of 2 has
been established by elemental analysis, IR, NMR spectroscopy, and X-ray crystallography. The
structure consists of polymeric chains and the molecular structure of two units of the polymer
{[(pyS)2CHCO2]Sn(CH3)3}n · CHCl3 with labelling for the main atoms is shown in Fig. 49. The
geometry of [(pyS)2CHCO2]Sn(CH3)3 is similar in the two independent unit. The tin atom is fivecoordinated, being bonded to two oxygen atoms and three methyl groups, respectively. The
coordination sphere is essentially distorted trigonal bi-pyramidal with the three equatorial positions
being taken up by the methyl substituents and the two axial positions being occupied by oxygens (O–
Sn–O = 169.9(3), averaged angle). In this mode the tin atom has the least electronegative groups in the
equatorial position and the electronegative oxygens in the axial position. The Sn–O distances are nonequivalent with the Sn–O (carboxyl) being slightly longer (2.512(8) Å, averaged bond length) than the
other (2.182(8) Å, averaged bond length). Thus the R–CO2 does not function as symmetric bridging
ligand. Because of the variation of the bond distances the tin is displaced from the equatorial plane of
155
the three methyl groups towards the covalently bond oxygen by about 0.15(1) Å. The C–Sn–C angles
ranging from 110.7(6) to 128.3(6).
Fig. 49. Molecular structure of two units of the polymer {[(pyS)2CHCO2]Sn(CH3)3}n · CHCl3, (including the equivalent
O2*, 1 + x, y, z) with 50% displacement ellipsoids and labelling of atoms around the tin atoms.
In the chain structure the carboxylate unit functions as a bridging ligand and connects two different tin
centers in a intermolecular manner. The preference for the chain structure seems to be the natural
consequence of the principles of five-coordination. In this mode the tin atom is in a trigonalbipyramidal geometry and has the least electronegative groups in the equatorial position and the
electronegative oxygens in the axial position. In solution the polymeric structure breaks down to
monomeric structure (even in a non-coordinating solvent such as CDCl3), as evidenced by 119Sn NMR.
The polymeric chains are along the a axis and form channels occupied by the solvent molecules, as
illustrated in Fig. 50, where the projection on the ac plane of the unit cell is shown. The two pyridine
rings of the two independent [(pyS)2CHCO2] moieties make a dihedral angle of 96.1(5) and 80.4(5),
respectively, and form the walls of the channels. Short contact is present between nitrogen atom of a
pyridine ring and the carbon atom of the chloroform (N1–C31(x, y, z − 1) = 3.39(3) Å).
Fig. 50. Projection on the ac plane of the polymeric complex {[(pyS)2CHCO2]Sn(CH3)3}n · CHCl3.
156
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