Metal complexes of cyclic hydroxamates. Synthesis and crystal structures of 3-hydroxy-2-methyl-3H-quinazolin-4-one (ChaH) and of its Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) complexes

Article abstract of DOI:10.1016/j.ica.2010.12.047

The attempted acetylation of anthranilic hydroxamic acid (2-aminobenzohydroxamic acid) as a possible dual inhibitor of the catalytic sites in prostaglandin-H-synthase (PGHS) gave the cyclic hydroxamic acid 3-hydroxy-2-methyl-3H-quinazolin-4-one (ChaH) which was characterised by spectroscopy and X-ray crystallography. The length of the hydroxamic acid C-N bond, 1.3998(17) ?, in ChaH is longer than normal (～1.33 ?) indicative of reduced delocalisation of the nitrogen lone pair of electrons into the hydroxamic acid π system. This is confirmed by the appearance of the ν(CO) band at a considerably higher wavenumber in the IR spectrum than normal. The complexes Fe(Cha)₂(Cl)(H₂O) ·⁷/₂H₂O, Co(Cha)₂(EtOH) ₂, Ni(Cha)₂(EtOH)₂, Cu(Cha)(H₂O)(Cl) and Zn(Cha)₂(H₂O), have been synthesised and their structures determined by X-ray crystallography. The X-ray data confirmed coordination by Cha^- through the carbonyl and deprotonated hydroxamate oxygen in all cases. The M-O (hydroxamate) bonds are shorter than the M-O (carbonyl) bonds by between 0.0930 ? for the Co(II) complex and 0.0448 ? for the Ni(II) complex. The geometries of all complexes conform to the coordination requirements of the particular metal ion involved. Speciation studies for ChaH and its complexes with Ni(II) and Zn(II) were carried out using pH-metric methods. The results show that ChaH is much more acidic than related acyclic hydroxamic acids and that its metal complexes are correspondingly less stable.

Full text of DOI:10.1016/j.ica.2010.12.047

Inorganica Chimica Acta 368 (2011) 58–66
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Metal complexes of cyclic hydroxamates. Synthesis and crystal structures
of 3-hydroxy-2-methyl-3H-quinazolin-4-one (ChaH) and of its Fe(III), Co(II),
Ni(II), Cu(II) and Zn(II) complexes
a
a,1
a
b
c
Ahmed Alagha , Laavanya Parthasarathi , Declan Gaynor , Helge Müller-Bunz , Zoya A. Starikova ,
d
a
a
a,
⇑
Etelka Farkas , Eimear C. O’Brien , Marie-Jose Gil , Kevin B. Nolan
a
Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, St. Stephen’s Green, Dublin 2, Ireland
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
X-Ray Structural Centre, Chemistry and Material Sciences Division, Russian Academy of Sciences Institute of Organoelement Compounds, 28 Vavilov St., B-334,
b
c
Moscow 119991, Russia
d
Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The attempted acetylation of anthranilic hydroxamic acid (2-aminobenzohydroxamic acid) as a possible
dual inhibitor of the catalytic sites in prostaglandin-H-synthase (PGHS) gave the cyclic hydroxamic acid
Received 22 October 2010
Accepted 18 December 2010
Available online 28 December 2010
3-hydroxy-2-methyl-3H-quinazolin-4-one (ChaH) which was characterised by spectroscopy and X-ray
crystallography. The length of the hydroxamic acid C–N bond, 1.3998(17) Å, in ChaH is longer than nor-
mal (ꢀ1.33 Å) indicative of reduced delocalisation of the nitrogen lone pair of electrons into the hydroxa-
Keywords:
mic acid
p system. This is confirmed by the appearance of the m(C@O) band at a considerably higher
Cyclic hydroxamic acid
Metal complexes
X-ray structures
Speciation
7
wavenumber in the IR spectrum than normal. The complexes Fe(Cha)
2
(Cl)(H
2
O)ꢁ /
2 2 2 2
H O, Co(Cha) (EtOH) ,
Ni(Cha) (EtOH) , Cu(Cha)(H O)(Cl) and Zn(Cha) (H O), have been synthesised and their structures deter-
2
2
2
2
2
-
mined by X-ray crystallography. The X-ray data confirmed coordination by Cha through the carbonyl and
deprotonated hydroxamate oxygen in all cases. The M–O (hydroxamate) bonds are shorter than the M–O
Stability
(carbonyl) bonds by between 0.0930 Å for the Co(II) complex and 0.0448 Å for the Ni(II) complex. The
geometries of all complexes conform to the coordination requirements of the particular metal ion
involved. Speciation studies for ChaH and its complexes with Ni(II) and Zn(II) were carried out using
pH-metric methods. The results show that ChaH is much more acidic than related acyclic hydroxamic
acids and that its metal complexes are correspondingly less stable.
Ó 2010 Elsevier B.V. All rights reserved.
1
. Introduction
nectedactivesites [13], a cyclooxygenase site(COX), whichcatalyses
the addition of two oxygen molecules to arachidonic acid and a spa-
Hydroxamic acids are a family of weak organic acids of general
tially distinct peroxidase site (POX), which catalyses the reduction of
a hydroperoxide group to the corresponding alcohol. As partof a pro-
gramme to develop new anti-inflammatory agents we have synthes-
ised acetylated salicylhydroxamic acids which, like aspirin, inhibit
the COX site [11] and anthranilic hydroxamic acids (2-amin-
obenzohydroxamic acids) which inhibit the POX site [12].
As a logical extension to this work we attempted the acetylation
of anthranilic hydroxamic acid, 1, as a possible dual COX/POX site
inhibitor. This however afforded not the acetylated derivative but
instead the cyclic hydroxamic acid 3-hydroxy-2-methyl-3H-
quinazolin-4-one (ChaH), 2, Scheme 1, a compound previously re-
ported [14]. Although some naturally occurring cyclic hydroxamic
acids such as the antibiotics aspergillic acid and norcadamine are
known [15] there have been relatively few comparisons of their
complexing properties with those of related acyclic hydroxamates
0
formula, RC(O)N(R )OH which are used as siderophores by bacteria
for the uptake of iron [1–3]. Hydroxamic acids are also nitric oxide
donors [4], are inhibitors of enzymes such as peroxidises [5], ureases
[
6], matrix metalloproteinases [7] and others [1a] and act as hypo-
tensive [8], antibacterial, anticancer, antibiotic and antifungal
agents [9]. Many of the above properties of hydroxamic acids are
due to their metal-binding abilities which have been extensively
studied and which are wide and varied [1,10]. We have recently
investigated hydroxamic acids as inhibitors of the enzyme prosta-
glandin-H-synthase (PGHS), alsocalled cyclooxygenase [11,12]. This
enzyme catalyses the first two steps in the biotransformation of ara-
chidonic acid to prostaglandin hormones. PGHS possesses two con-
⇑
Corresponding author.
E-mail address: kbnolan@rcsi.ie (K.B. Nolan).
Present address: Smurfit Institute of Genetics, Trinity College, Dublin 2, Ireland.
[
16]. Herein we report the X-ray structures of ChaH and of its
1
complexes with Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) as well as
0
020-1693/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2010.12.047

A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
59
O
C@O bond due to competition for this lone pair from the imine
group. The H NMR spectrum showed a singlet at 2.52 ppm corre-
O
1
OH
OH
3
sponding to the CH group, a multiplet for four aromatic protons
N
H
CH COCl
3
N
between d 7.51 ppm and d 8.12 ppm and a very broad singlet at d
1
3
1
1.62 ppm corresponding to the OH group. The C NMR spectrum
displayed signals at d 20.24 ppm for the CH group, d 133.90 ppm
for the phenyl carbon attached to the carbonyl group,
pyridine
NH2
3
N
d
1
2
146.14 ppm for the phenyl carbon attached to the nitrogen and sig-
nals for the remaining phenyl CH groups at d 121.35, 125.77,
Scheme 1
1
26.01 and 126.71 ppm. The C@N and C@O signals appeared at d
54.09 and d 157.66 ppm, respectively.
1
Crystals of 2 suitable for X-ray analysis were obtained by
speciation studies of the ligand and its complexes with Ni(II) and
Zn(II), the only two of these ions which for solubility reasons per-
mitted this study. These ions were chosen because their complexes
with acyclic hydroxamates have been widely reported.
This study represents the most detailed to date of metal com-
plexes of a cyclic hydroxamate. It reports interesting structural fea-
tures of the ligand and rationalizes the structures of the complexes
in terms of recently reported [17,18] coordination requirements of
the complexed metal ions. Furthermore the solid state studies are
complemented by solution speciation studies in the case of the
ligand and two of the metal ions for which solubility permitted.
recrystallisation from ethanol. The structure of 2 is shown in
Fig. 1 with selected bond lengths and angles in the legend and crys-
tal data in Table 2. This confirms the cyclic structure of the
hydroxamic acid. The key feature of the structure is the length of
the N(2)–C(3) bond, 1.3998(17) Å, which is significantly longer
than normal (ꢀ1.33 Å, [19]) consistent with the IR evidence for re-
duced
p electron delocalisation from N(2) to the hydroxamate
group. This effect is also seen in the C(3)–O(2) bond length,
.2149(18) Å, which is shorter than normal, (ꢀ1.25 Å, [19]). That
instead there is significant delocalisation from N(2) towards
1
p
2
. Results and discussion
2.1. Cha, (2), formation and structure
With the intention of synthesising a possible dual COX/POX site
inhibitor of PGHS we attempted the acetylation of anthranilic
hydroxamic acid, 1, but instead of the acetylated derivative we ob-
tained the cyclic hydroxamic acid 3-hydroxy-2-methyl-3H-quinaz-
olin-4-one (ChaH), 2, Scheme 2. The proposed mechanism for
formation of this compound, Scheme 2, involves acetylation of
the amino group followed by nucleophilic attack by the hydroxam-
ato nitrogen on the acetyl carbonyl group giving a tetrahedral
intermediate which following further acetylation and loss of acetic
acid gives product 2.
ꢂ1
The IR spectrum of 2 displayed salient bands at 3470 cm cor-
ꢂ1
responding to
m
(OH), a strong absorption at 1682 cm
due to
m
1
(C@O) of the hydroxamate group, and a strong
612 cm . The m(C@O) band is at a considerably higher wavenum-
m
(C@N) band at
ꢂ1
ber than normally observed for hydroxamic acids and this may be
due to reduced delocalisation of the nitrogen lone pair into the
hydroxamate
p
system and thereby increased
p
character of the
O
O
N
OH
OH
N
H
(Ac) O
N
H
2
Pyridine
NH2
H
O
1
(
2
Ac) O
Fig. 1. The asymmetric unit of 2 and molecular packing viewed down the a-axis.
Selected bond lengths (Å) and angles (°): C(3)–O(2) 1.2149(18), N(2)–O(1)
1.3823(14), N(1)–C(1) 1.3037(18), C(1)–N(2) 1.3689(17), N(2)–C(3) 1.3998(17),
C(3)–C(4) 1.4608(17), N(1)–C(9) 1.3906(16); O(1)–N(2)–C(3) 116.60(11), O(2)–
C(3)–N(2) 121.54(12), C(1)–N(1)–C(9) 118.67(11), N(1)–C(9)–C(4) 121.84(11),
O
N
N
O
OH
OH
N(1)–C(1)–C(2)
120.34(12),
C(5)–C(4)–C(3)
119.52(12),
N(2)–C(1)–C(2)
-
HOAc
N
117.70(12), N(1)–C(1)–N(2) 121.95(12), C(1)–N(2)–O(1) 117.90(11), C(1)–N(2)–
N
H
OAc
C(3) 125.12(11), O(2)–C(3)–C(4) 125.99(12), N(2)–C(3)–C(4) 112.47(11), N(1)–
C(9)–C(8) 119.15(12), C(9)–C(4)–C(3) 119.88(12). Dashed lines represent the
O–HꢁꢁꢁN and C–HꢁꢁꢁO interactions within the lattice: O–H = 0.90(3), d = 1.75(3) Å,
D = 2.645(2) Å, h = 171(3)°, C–H2A = 0.9804 Å, d = 2.4718Å, D = 3.310(2) Å, h =
143.23 (3)°, C–H2C = 0.9804 Å, d = 2.4717 Å, D = 3.410(2) Å, h = 160.29°.
2
Scheme 2

6
0
A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
the imine group, is confirmed by the C(1)–N(2) bond length,
.3689(17) Å, which is much shorter than a C–N single bond [19],
2.2. Synthesis and structures of metal complexes of 2
1
and the C(1)–N(1) bond length, 1.3037(18) Å, which is longer than
normally observed for an imine. Intermolecular interactions in-
volve hydroxamate OH to imine N and carbonyl oxygen to methyl
H (H2A, H2C) hydrogen bonding. These interactions generate an
infinite one dimensional chain along the base vector [0 1 0] giving
the supramolecular architecture.
Metal complexes of 2 were prepared by addition of an excess of
2 in hot ethanol to aqueous solutions of the metal chloride or the
acetate in the case of Zn(II). This resulted in the title complexes
either as crystals suitable for X-ray structure determination or as
precipitates which after filtration gave filtrates from which
suitable crystals were obtained. Average differences between
Fig. 2. (a) The asymmetric unit of 3 and (b) molecular packing viewed down the b-axis. Selected bond lengths (Å) and angles (°): Fe(1)–O(1) 1.964(2), Fe(1)–O(2) 2.048(2),
0
0
Fe(1)–O(3) 1.981(2), Fe(1)–O(4) 2.050(2), Fe(1)–O(5) 2.093(6), Fe(1)–O(5 ) 2.149(6), Fe(1)–Cl(1) 2.189(3), Fe(1)–Cl(1 ) 2.313(2), O(1)–N(3) 1.362(3), O(2)–C(4) 1.274(3), N(1)–
C(2) 1.287(4), C(2)–N(3) 1.385(4), N(3)–C(4) 1.350(4); O(1)–Fe(1)–O(3) 170.72(9), O(5)–Fe(1)–O(2) 79.18(8), O(3)–Fe(1)–O(2) 95.11(9), O(1)–Fe(1)–O(4) 93.97(8), O(3)–
0
Fe(1)–O(4) 78.61(8), O(2)–Fe(1)–O(4) 89.92(8), O(1)–Fe(1)–O(5) 103.9(2), O(3)–Fe(1)–O(5) 82.0(2), O(2)–Fe(1)–O(5) 79.65(17), O(4)–Fe(1)–O(5) 157.1(2), O(1)–Fe(1)–O(5 )
0 0 0
2.82(18), O(2)–Fe(1)–O(5 ) 161.18(18), O(3)–Fe(1)–O(5 ) 102.00(18), O(4)–Fe(1)–O(5 ) 85.87(17), O(1)–Fe(1)–Cl(1) 94.37(8), O(3)–Fe(1)–Cl(1) 92.15(9), O(2)–Fe(1)–Cl(1)
8
1
1
0
0
0
0
70.46(9), O(4)–Fe(1)–Cl(1) 97.59(10), O(5)–Fe(1)–Cl(1) 95.27(19), O(1)–Fe(1)–Cl(1 ) 95.69(8), O(2)–Fe(1)–Cl(1 ) 98.37(8), O(3)–Fe(1)–Cl(1 ) 92.36(8), O(4)–Fe(1)–Cl(1 )
0
0
68.29(8), O(5 )–Fe(1)–Cl(1 ) 88.78(17), O(1)–N(3)–C(2) 119.3(2), O(2)–C(4)–N(3) 117.7(3).

A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
61
calculated and found microanalyses ranged from 0.28 for com-
and [1 0 0] and along the plane (0 1 0), Fig. 2(b). The Fe–
O(hydroxamate) bond lengths, 1.964(2) and 1.981(2) Å, as ex-
pected on the basis of donor atom charges are shorter than the
pound 9 to 0.38 for compound 3. The IR spectra of all of the com-
ꢂ1
plexes showed
m
(C@O) hydroxamate bands at ꢀ1607–1625 cm
which is in the normal range for hydroxamate complexes and is
Fe–O(carbonyl) lengths, 2.048(2) and 2.050(2) Å, giving
ues of 0.084 Å and 0.069 Å. These bond lengths are similar to the
corresponding bonds in Fe(C CONHO) [20], which are in the
DFe–O val-
much lower than the free ligand indicative of normal delocalisation
of the nitrogen lone pair into the hydroxamate
p
system.
H
6 5
3
range 1.9689(18)–1.9753(19) Å for the Fe–O(hydroxamate) bonds
and 2.0356(18)–2.0585(17) Å for the Fe–O(carbonyl) bonds. giving
DFe–O values of 0.0824, 0.0641 and 0.0896 Å. The difference in the
7
2
.2.1. Fe(Cha)
2
(Cl)(H
2
O)ꢁ /
2 2
H O, (3)
Dark-brown crystals of 3 suitable for X-ray analysis were ob-
tained from the reaction mixture after two weeks. The structure
of 3 is shown in Fig. 2(a) with selected bond lengths and angles
in the legend and crystal data in Table 2. The crystal structure
shows that the iron(III) is in a pseudo-octahedral environment sur-
rounded by two cis hydroxamate ligands displaying normal biden-
tate O,O-coordination The two remaining cis coordination sites are
occupied by a water molecule and a chloride ion. These two sites
exhibit disorder with occupation equally distributed with chloride,
Fe–Cl bond lengths, 2.189(3), and 2.313(2) Å, the latter of which is
close to the reported average for Fe(III)–Cl bonds [17], may be due
to a trans influence, the longer bond being trans to the hydroxa-
mate whilst the shorter is trans to the neutral carbonyl oxygen.
The Fe–O(water) bond lengths 2.093(6) and 2.149(6) Å are close
to the reported average for Fe(III)–O(water) bonds [17]. The
hydroxamate N to carbonyl C bond, N(12)–C(13) 1.361(4) Å, is
shorter than the corresponding bond in 2 consistent with increased
delocalisation of the nitrogen lone pair of electrons into the
0
0
Cl/Cl , or water, O5/O5 . Intermolecular hydrogen bonding involv-
ꢂ
ing lattice waters O1W–O5W with imine N, the Cl ligand and
hydroxamate p system in the complex. The bond angles around
other lattice waters generate an infinite two dimensional supramo-
lecular structure with large cavities along the base vectors [0 0 1]
the metal 78.61(8)–103.9(2)° and 161.18(18)–170.46(9)° indicate
considerable distortion from octahedral geometry.
Fig. 3. The asymmetric units of (a) 5 and (b) 6 showing the atomic labelling sequence. Selected bond lengths (Å) and angles (°): (a) Co–O(1) 2.0323(8), Co–O(2) 2.1253(8), Co–
O(3) 2.1126(8), O(1)–N(1) 1.3576(10), N(1)–C(9) 1.3806(12), C(9)–O(2) 1.2501(12), N(1)–C(1) 1.3752(12), C(1)–N(2) 1.3083(13), O(1)–Co–O(1a) 180.0, O(1)–Co–O(3)
8
8
8.48(3), O(1a)–Co–O(3) 91.52(3), O(1)–Co–O(3a) 91.52(3), O(1a)–Co–O(3a) 88.48(3), O(3)–Co–O(3a) 180.0, O(1)–Co–O(2) 78.96(3), O(1a)–Co–O(2) 101.04(3), O(3)–Co–O(2)
7.33(3), O(3a)–Co–O(2) 92.67(3), O(1)–Co–O(2a) 101.04(3), O(1a)–Co–O(2a) 178.96(3), O(3)–Co–O(2a) 192.67(3), O(3a)–Co–O(2a) 187.33(3), O(2)–Co–O(2a) 180.0, O(2)–
C(9)–C(8) 125.23(9), O(2)–C(9)–N(1) 119.55(9), O(1)–N(1)–C(9) 118.37(8); (b) Ni–O(1) 2.0181(10), Ni–O(2) 2.0629(10), Ni–O(3) 2.0794(11), O(1)–N(1) 1.3565(14), N(1)–C(9)
1
8
9
.3778(17), C(9)–O(2) 1.2509(17), N(1)–C(1) 1.3739(17), C(1)–N(2) 1.3070(17), O(1)–Ni–O(1a) 180.0, O(1)–Ni–O(3) 88.38(4), O(1a)–Ni–O(3) 91.62(4), O(1a)–Ni–O(3a)
8.38(4), O(1)–Ni–O(2) 80.68(4), O(1a)–Ni–O(2) 99.32(4), O(2)–Ni–O(3) 87.75(5), O(3a)–Ni–O(2) 92.67(3), O(1)–Ni–O(2a) 99.32(4), O(1a)–Ni–O(2a) 80.68(4), O(2)–Ni–O(3a)
2.25(5), O(3)–Ni–O(2a) 192.67(3),

6
2
A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
2
.2.2. Co(Cha)
2
(C
OH)
2
H
5
OH)
(6)
2
ꢁH
2
O, (4), Co(Cha)
2
(C
2
H
5
OH)
2
, (5) and
In complex 8 the Cu(II) is in a square pyramidal environment,
which is the most commonly reported for this metal ion [17,21],
containing an O,O-bonded hydroxamate ligand, a bridging chloride
and a water ligand in the basal plane and a bridging chloride in the
axial position. As in the previously discussed and other complexes
[20], the M–O (hydroxamate) bond, 1.9198(15) Å, is shorter than
Ni(Cha) (C
2
H
2 5
2
The cobalt complexes 4 and 5 were obtained as a red precipitate
and red crystals, suitable for X-ray analysis, respectively from the
reaction mixtures after a period of 2 months. Green crystals of
the nickel complex 6 were obtained after a similar period. The
structures of 5 and 6, which are isostructural, are shown in Fig. 3
with selected bond lengths and angles in the legend and crystal
data in Table 2.
In complexes 5 and 6 the metal ions are in pseudo-octahedral
environments, which is the most commonly reported for Co(II)
and one of the two most commonly reported for Ni(II) [17], con-
taining two hydroxamate ligands displaying normal bidentate
O,O-coordination and two trans ethanol ligands axially coordi-
nated. As in complex 3 and in complexes of these metal ions with
other hydroxamate ligands [20], the M–O(hydroxamate) bonds,
the M–O (carbonyl) bond 1.9944(14) Å,
D(Cu–O) = 0.0746 Å. The
Cu–O (water) bond length 1.9386(17) Å falls in the reported range
for Cu–O (water) bonds basally coordinated in square pyramidal
copper(II) complexes. The Cu–Cl (basal) and Cu–Cl (axial) bond
lengths, 2.2256(6) and 2.7080(6) Å are similar to those reported
for copper(II) complexes, e.g. [Cu
2
(
l
-Cl)
2
(pabh)
2
]ꢁ4H
2
O (Hpabh is
pyridine-2-carbaldehyde-benzoylhydrazone) having both these
types of bridging chloride ligand, 2.2177(11) Å, 2.7821(13) Å [22].
The O–Cu–O and O–Cu–Cl bond angles 82.81(6)–95.92(5)° confirm
the distorted square pyramidal geometry.
2
.0323(8) for Co, 2.0181(10) Å for Ni, are shorter than the M–
O(carbonyl) bonds, 2.1253(8) Å for Co, 2.0629(10) for Ni giving
Co–O and Ni–O of 0.0930 and 0.0448 Å, respectively. The M–
D
D
2
.2.4. [Zn(Cha)
2
]
2
ꢁH
2
O, (9)
O(EtOH) bonds lengths are 2.1126(8) Å for Co and 2.0794(11) for
Ni similar to the reported averages for octahedral complexes of
these metal ions with neutral oxygen donor atoms [17,18]. As is
usually observed the Ni–O bond lengths are shorter than the corre-
sponding Co–O bond lengths consistent with the higher charge
density of Ni(II) relative to Co(II). The O–M–O bond angles in both
complexes indicate relatively minor distortions from octahedral
geometry. In both 5 and 6 intermolecular hydrogen bonding
involving the imine nitrogens and EtOH ligands generate infinite
two dimensional networks along the base vectors [0 0 1] and
Complex 9 was obtained as colourless crystals suitable for X-ray
structure determination by allowing the filtrate from the reaction
mixture to stand at room temperature for 1 week. The structure
of 9 is shown in Fig. 5 with selected bond lengths and angles in
the legend and crystal data in Table 2.
In complex 9 the Zn(II) is in a square pyramidal environment,
containing O,O-bonded hydroxamate ligands in the basal plane
and a water molecule located axially at 2.0167(15) Å. As in the pre-
viously discussed and other complexes [20] the Zn–O (hydroxa-
mate) bond, 1.9954(13) Å, is shorter than the Zn–O (carbonyl)
[
0 1 0] and through the plane (ꢂ1 0 0).
bond 2.0789(13) Å, giving
DZn–O of 0.0835 Å. The Zn–O (water)
bond length 2.0167(15) Å falls in the reported range for Zn–O
(water) bonds in zinc(II) complexes. The O–Zn–O bond angles in
the basal plane range from 80.23(5) to 95.66(5)° indicating consid-
erable distortion from square pyramidal geometry. The intermo-
lecular hydrogen bonding involving O–HꢁꢁꢁO and O–HꢁꢁꢁN
interactions within the lattice generate an infinite one dimensional
chain along the base vector [0 1 0]. These aggregates form two
clusters each generating an infinite two dimensional network
along the base vector [0 1 0] and [0 0 1] and along the plane (1 0 0).
2
.2.3. Cu(Cha)
Complex 7 was obtained as a green precipitate immediately
after addition of CuCl O to a hot solution of 2 in ethanol. Single
2 2
, (7) and Cu(Cha)H O(Cl), (8)
2
ꢁ2H
2
crystals of 8 suitable for X-ray structure determination were ob-
tained by allowing the filtrate from the reaction mixture to stand
at room temperature for two months. The structure of 8 is shown
in Fig. 4 with selected bond lengths and angles in the legend and
crystal data in Table 2.
Fig. 4. The asymmetric unit of 8 showing the atomic labelling sequence. Selected bond lengths (Å) and angles (°): Cu–O(1) 1.9198(15), Cu–O(2) 1.9944(14), Cu–O(3)
.9683(17), Cu–Cl 2.2256(6), Cu–Clb 2.7080(6), N(1)–O(1) 1.362(2), N(1)–C(9) 1.355(3), O(2)–C(9) 1.272(3), N(1)–C(1) 1.383(3), C(1)–N(2) 1.296(3), C(8)–C(9) 1.431(3); O(1)–
Cu–O(3) 86.63(7), O(1)–Cu–O(2) 82.81(6), O(1)–Cu–Cl 164.90(5), O1–Cu–Clb 95.92(5), O2–Cu–Clb 86.10(4), O3–Cu–Clb 96.45(6), O(3)–Cu–O(2) 169.34(7), O(2)–Cu–Cl
4.79(5), O(3)–Cu–Cl 95.03(6), O(1)–N(1)–C(1) 118.08(17), C(9)–N(1)–O(1) 118.06(17), O(2)–C(9)–N(1) 117.79(19), O(2)–C(9)–C(8) 126.32(19), N(1)–C(1)–C(2) 116.55(19).
1
9

A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
63
Fig. 5. The asymmetric units of 9 showing the atomic labelling sequence. Selected bond lengths (Å) and angles (o): Zn–O(1) 1.9954(13), Zn–O(2) 2.0789(13), Zn–O(5)
.0167(15), O(1)–N(1) 1.3551(19), N(1)–C(1) 1.370(2), C(1)–C(2) 1.492(3), N(1)–C(9) 1.375(2), C(9)–O(2) 1.252(2), C(1)–N(2) 1.304(2), O(1)–Zn–O(4) 140.06(6), O(1)–Zn–
2
O(5) 104.00(6), O(1)–Zn–O(2) 80.63(5), O(1)–Zn–O(3) 95.66(5), O(5)–Zn–O(2) 97.30(6), O(4)–Zn–O(2) 91.11(5), O(5)–Zn–O(3) 100.96(6), O(3)–Zn–O(2) 161.72(5), O(4)–Zn–
O(5) 115.83(6), O(4)–Zn–O(3) 80.23(5), O(2)–C(9)–C(8) 125.42(17), O(2)–C(9)–N(1) 119.16(17), O(1)–N(1)–C(9) 118.66(14).
2
.3. Speciation in solution
ues and stability constants are listed in Table 1. The corresponding
data for anthranilic hydroxamic acid, previously determined [5b]
as a reference are also included. Unfortunately, values for the
Fe(III), Co(II) and Cu(II) complexes of 2 could not be obtained due
Species distribution for Cha, 2, complexes of Ni(II) and Zn(II) ob-
a
tained from pH-metric data are presented in Fig. 6 and the pK val-
to precipitation of the complexes at very low pH values.
0
The cyclic hydroxamic acid 2 (HA ), is a monobasic acid, the pK
a
of which, from analysis of pH-metric data was found to be 6.05
ꢂ3
(
0.02) at 25 °C, ionic strength 0.2 mol dm KCl. Hence it is much
more acidic than the corresponding group in anthranilic hydroxa-
mic acid, 1 (HA), pK 8.76 (0.04) and other aromatic hydroxamic
acids such as benzohydroxamic acid, pK 8.71 (0.03) [5b]. The in-
a
a
creased acidity of the cyclic hydroxamic acid may be due to the
presence of the electron withdrawing ring imine N and/or greater
stabilization of the conjugate base relative to the acid by increased
delocalisation of the nitrogen lone pair into the hydroxamate
group
p system.
0
In both the Ni(II) and Zn(II) systems containing 2 (HA ) the main
species in solution at pH 5.5 are the 1:1 complexes, the log b values
of which are given in Table 1. These values are lower than those for
Table 1
Stability constants (log bpqr)a of the H , Ni(II) and Zn(II) complexes of Cha (2,
+
0
HA ) and anthranilic hydroxamic acid (1, HA) at T = 25.0 °C and
ꢂ3
I = 0.20 mol dm KCl (sds given in parentheses).
0
Species
HA
Cha (2, HA ) Anthranilic hydroxamic acid (1, HA)
–
8.76(0.04)
H
HA
2
A
–
11.49(0.04)
–
5.16(0.07)
–
0
6.05(0.02)
–
3.74(0.02)
6.42(0.02)
+
[
[
[
Ni(A)]
Ni(A )]
Ni(A )
0
0
+
2
]
–
NiAH-1
NiA H-1
–
ꢂ2.05(0.11)
0
ꢂ3.24(0.02)
–
+
[
[
[
[
[
[
Zn(A)]
Zn(A )]
–
4.97(0.08)
–
9.09(0.08)
–
0
+
3.72(0.02)
–
6.71(0.02)
–
ꢂ3.65(0.02)
Zn(A)
Zn(A )
2
]
0
2
]
Zn(A)
Zn(A Hꢂ1)]
2
H
ꢂ1]ꢂ
ꢂ1.05(0.04)
0
–
Fig. 6. Concentration distribution curves of the species present in (a) the nickel(II) –
cyclic hydroxamic acid (1:2) and (b) zinc(II) – cyclic hydroxamic acid (1:2) systems.
a
log bpqr values refer to the equilibrium pM + qA + rH = MpAqHr.

6
4
A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
Table 2
Crystal data collection and refinement details.
Compound
2
3
5
6
8
9
Empirical formula
C
H
9 8
2
N O
2
C
18
H
23
4
N O
8.5ClFe
C
22
H
26
4
N O
6
Co
C
22
H
26
4
N O
6
Ni
C
9
H
13
N
2
O
5
ClCu
C
20 22 4 6
H N O Zn
M
T (K)
k (Å)
Space group
a (Å)
b (Å)
c (Å)
a (°)
r
176.17
100(2)
522.70
113(2)
0.71073
C2/c
16.031(7)
25.745(12)
12.726(6)
90
501.40
100(2)
0.71073
501.18
100(2)
0.71073
328.20
100(2)
479.79
100(2)
0.71073
C2/c (#15)
15.594(2)
15.511(2)
17.437(2)
90
0.71073
P2 (#4)
0.71073
P2 /c (#14)
1
P2
1
/c (#14)
1
P2 /c (#14)
1
4.3271(6)
9.3902(13)
9.6743(13)
90
9.3627(13)
15.930(2)
7.8111(11)
90
9.3851(8)
15.8715(13)
7.7661(7)
90
9.5088(7)
18.4349(13)
6.8155(5)
90
b (°)
95.837(3)
90
391.05(9)
2
1.496
0.109
125.634(0)
90
4269(3)
8
1.613
0.71072
2160
111.027(2)
90
1087.4(3)
2
1.531
0.837
110.967(2)
90
1080.21(16)
2
1.541
0.947
524
90.643(1)
90
1194.64(15)
4
1.825
2.066
111.025(3)
90
3936.7(10)
8
1.619
1.296
1984
c
(°)
3
V (Å )
Z
ꢂ3
Dcalc (g cm
)
ꢂ1
l
(mm
)
F(0 0 0)
184
522
668
Crystal size/mm
0.50 ꢃ 0.20 ꢃ 0.10
0.1 ꢃ 0.2 ꢃ 0.4
0.70 ꢃ 0.60 ꢃ 0.60
0.40 ꢃ 0.30 ꢃ 0.03
0.60 ꢃ 0.05 ꢃ 0.02
0.60 ꢃ 0.40 ꢃ 0.30
Goodness-of-fit (GOF)a
1.036
0.958
1.051
1.049
1.119
1.039
Final R indices [I > 2
R indices (all data)
r
(I)]
R
1
= 0.0398;
wR = 0.1035
= 0.0411,
wR = 0.1046
0.535 and ꢂ0.158
R
1
= 0.0520;
wR = 0.1239
= 0.1020;
wR = 0.1459
1.031 and ꢂ0.624
R
1
= 0.0318;
wR = 0.0833
= 0.0356,
wR = 0.0857
0.643 and ꢂ0.256
R
1
= 0.0318;
wR = 0.0890
= 0.0354,
wR = 0.0914
0.531 and ꢂ0.223
R
1
= 0.0286;
wR = 0.0628
= 0.0338,
wR = 0.0647
0.441 and ꢂ0.265
R
1
= 0.0283;
wR = 0.0702
= 0.0343,
wR = 0.0727
0.385 and ꢂ0.273
2
2
2
2
2
2
R
1
R
1
R
1
R
1
R
1
R
1
2
2
2
2
2
2
Largest diff. peak and hole
ꢂ3
(
e nm
)
a
GOF ¼ S ¼ fS½wðFo ꢂ F Þ ꢄ=ðn ꢂ pÞg1=2.
2
2
2
c
anthranilic hydroxamic acid, 1 (HA),
D
(log b) = 1.42 for Ni(II) and
4.2. Syntheses
4.2.1. Anthranilic hydroxamic acid, (1)
1
.25 for Zn(II) which reflects the decreased basicity of the hydroxa-
0
mate ligand derived from 2 (HA ). The stability constants of the 1:1
complexes of both metal ions are very similar which is frequently
observed in Ni(II) and Zn(II) hydroxamate complexes [23]. At high-
This was synthesised using a literature reported method [24].
er pH the formation of 2:1 complexes Ni–(2)
2
and Zn–(2)
2
followed
(OH) are
4.2.2. 3-Hydroxy-2-methyl-3H-quinazolin-4-one (ChaH), (2)
3
by the hydroxo complexes Ni–(2)
2
(OH) and Zn–(2)
2
1 (2 g, 13.16 mmol) was dissolved in dry pyridine (20 cm ) un-
observed.
der an atmosphere of nitrogen and the solution was cooled to 0 °C
3
in an ice bath. Acetic anhydride (1.24 cm , 13.16 mmol) was then
added slowly via a syringe and the resulting solution was stirred
at 0 °C for 30 min and then at room temperature for 5 h. This pro-
3
. Conclusions
The cyclic hydroxamic acid, 2, reported in this work is much
duced a white precipitate which was washed with 5% HCl
3
(
2
3 ꢃ 30 cm ), then suspended in de-ionised water and stirred for
more acidic and forms less stable complexes than the related acy-
clic hydroxamic acid, anthranilic hydroxamic acid. The structures
of the complexes investigated conform to those predicted for the
particular metal ion involved. 2 was obtained following attempted
acetylation of anthranilic hydroxamic acid as part of our efforts to
synthesise dual COX and POX site inhibitors of prostaglandin-H-
synthase. The introduction of substituents on to the amino group
of the starting material may circumvent cyclisation and produce
an acyclic acetylated derivative.
h to remove remaining traces of pyridine. The precipitate was
collected by filtration, dried over P and recrystallised from min-
imum hot ethanol to give white crystals. Yield: 1.4 g, 61%. m.p.
2 5
O
2
4
3
1
7
7
9 8 2 2
74–276 °C. Elemental Anal. Calc. for 2, C H N O : C, 61.33; H,
.60; N, 15.90. Found: C, 60.79; H, 4.49; N, 15.75%. IR (KBr disc):
470br, 2571br, 1682vs, 1612s 1478s, 1463s, 1394s, 1239s,
ꢂ1
1
175s cm
.
6 3
H NMR (d -DMSO): d (ppm): 2.52 (s, 3H, CH ),
.51–7.47 (m, 1H, aromatic), 7.62 (d, J = 8.0 Hz, 1H, aromatic),
.77–7.81 (m, 1H, aromatic), 8.12 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H, aro-
1
3
matic), 11.62 (s, 1H, OH). C NMR (d
(CH ), 133.90, 146 (2C, phenyl), 121.35, 125.77, 126.01, 126.77
4CH, phenyl), 154.09 (C@N), 157.66 (C@O, amide). The crystals
6
-DMSO): d (ppm): 20.24
4
. Experimental
3
(
4.1. Materials
of 2 obtained from the recrystallisation were used for X-ray struc-
ture determination.
Methyl anthranilate, pyridine and acetic anhydride were all
7
purchased from Aldrich and used without further purification. IR
4.2.3. Fe(Cha)
FeCl
ꢁ6H
2 2 2 2
(Cl)(H O)ꢁ / H O, (3)
ꢂ1
3
spectra were recorded as KBr discs (4000–400 cm ) on a Mattson
3
2
O (0.139 g, 0.51 mmol) in water (10 cm ) was added
3
Genesis II CSI FTIR spectrometer and the spectra analysed using
WinFirst software. All KBr discs were made using FTIR grade KBr
to a solution of 2 (0.25 g, 1.56 mmol) in methanol (25 cm ) at
40 °C. The resulting dark brown solution was left to stand at room
temperature for 2 weeks during which time a dark brown crystal-
line product, suitable for X-ray structure determination was ob-
tained. This was filtered, washed with water and dried. Yield:
0.15 g, 0.24 mmol, 66%. Elemental Anal. (%) Calc. for 3,
1
purchased from Aldrich. H NMR spectra were recorded on a Bru-
1
3
ker DPX 400 NMR spectrometer which was also used to record
spectra at 101 MHz. Data were analysed using WIN NMR software.
The residual undeuterated DMSO signal at 2.505 ppm or the Me Si
C
4
signal were used as internal references. Elemental analysis (C, H, N,
Cl, Fe, Co, Ni, Cu and Zn) were performed at the Microanalytical
Laboratory, School of Chemistry and Chemical Biology, University
College Dublin.
18 23 4
C H N O8.5ClFe: C, 41.36; H, 4.40; N, 10.72; Cl, 6.80, Fe, 10.68.
Found: C, 41.01; H, 4.00; N, 9.97; Cl, 6.92; Fe, 10.39%. IR (KBr disc)
3500s and 3000s (N–H, O–H), 1625vs and 1575s (hydroxamate
CO), 1545vs (C–N).

A. Alagha et al. / Inorganica Chimica Acta 368 (2011) 58–66
65
4
.2.4. Co(Cha)
To a solution of CoCl
2
(C
2
H
5
OH)
2
ꢁH
2
O, (4), and Co(Cha)
2
(C
2
H
5
OH)
2
, (5)
electrode, in the pH range 2.0–11.5 using 25.0 cm3 solutions. The
electrode systems were calibrated by the method of Irving et al.
[26] so that pH-metric readings could be converted into hydrogen
ion concentrations. All pH-metric measurements were carried out
at 25.0 ± 0.1 °C and at an ionic strength of 0.2 mol dm KCl. The
concentrations of the ligand stock solutions were determined by
3
2
2
ꢁ6H O (0.05 g, 0.21 mmol) in water (3 cm )
was added with stirring a solution of 2 (0.16 g, 0.92 mol) in hot
ethanol (20 cm ). The reaction mixture was left to stand at room
temperature for 2 months during which time a red precipitate
was obtained. This was filtered, washed with ethanol and dried.
Yield: 0.09 g, 0.18 mmol, 86%. Elemental Anal. Calc. for 4,
3
ꢂ3
titration with KOH solution of known concentration. The metal
C
5
1
22
H
28
N
4
O
7
Co: C, 50.84; H, 5.45; N, 10.79, Co, 11.35. Found; C,
ion solutions were prepared from NiCl
2
ꢁ6H
2
O and zinc(II) oxide
0.71; H, 4.73; N, 11.24, Co, 11.32%. IR (KBr disc): 3067w,
622vs, 1577vs, 1477vs, 1397s, 1249s, 1179vs cm . Amongst
by dissolving the required amount of salt in distilled water or in
hydrochloric acid of known concentration, respectively [27]. The
concentrations of these stock solutions were determined via pre-
cipitation of the quinolin-8-olate or oxide.
ꢂ1
the precipitate described above a small quantity of red crystals of
Co(Cha) (C OH) , 5, deposited. These were successfully isolated
and were suitable for X-ray structure analysis.
2
2
H
5
2
a
To determine the pK value for the cyclic hydroxamic acid a
ꢂ3
ꢂ3
solution of the hydroxamic acid (ꢀ 1.7 ꢃ 10 mol dm ) in HCl
ꢂ3
ꢂ3
ꢂ3
4.2.5. Ni(Cha)
2 2
(C H
5
OH)
2
(6)
ꢁ6H
(ꢀ4.8 ꢃ 10 mol dm ) and 0.20 mol dm
KCl was prepared
O (0.05 g, 0.21 mmol) in water (3 cm3)
and titrated with a 0.20 mol dm
ꢂ3
KOH solution. The resulting
To a solution of NiCl
2
2
was added a solution of 2 (0.081 g, 0.46 mmol) in hot ethanol
titration data were then analysed using the SUPERQUAD computer
programme [28]. The stability constants for the Ni(II) and Zn(II) –
cyclic hydroxamic acid systems were determined by titration of a
3
(
20 cm ). The reaction mixture was left to stand at room tempera-
ture for 2 months during which time light green crystals of 6 suit-
able for X-ray structure analysis, were obtained. These were
collected by filtration and washed with ethanol. Yield: 0.06 g,
ꢂ3
ꢂ3
solution containing the hydroxamic acid (ꢀ 1.7 ꢃ 10 mol dm
)
and the metal ion in ratios of 1:2, 1:3 and 1:4 in HCl
ꢂ3
ꢂ3
ꢂ3
ꢂ3
0
5
1
1
.12 mmol, 57%. Elemental Anal. Calc. for 6, C22
0.87; H, 5.45; N, 10.79, Ni, 11.31. Found C, 50.89; H, 5.86; N,
1.20; Ni, 11.83%. IR (KBr disc): 3073br, 1607vs, 1577vs, 1472vs,
428s, 1378s, 1249s, 1179 vs cm
26
H N
4
O
6
Ni: C,
(ꢀ4.8 ꢃ 10 mol dm
)
and 0.20 mol dm
KCl with
a
0.20 mol dm KOH solution. The resulting titration data were ana-
lysed using the PSEQUAD computer programme [29]. Determination
of the stability constants of the Fe(III), Co(II), and Cu(II) – cyclic
hydroxamic acid complexes were not possible due to precipitation
of the metal complexes at very low pH values.
ꢂ1
.
4.2.6. Cu(Cha)
2
, (7) and Cu(Cha)H
2
O(Cl), (8)
3
To a solution of CuCl
2 2
ꢁ2H O (0.05 g. 0.29 mmol) in water (3 cm )
was added with stirring a solution of 2 (0.11 g, 0.64 mmol) in hot
ethanol (20 cm ). This resulted in the immediate formation of a
Acknowledgments
3
green precipitate of 7 which was collected by filtration and washed
with ethanol. Yield: 0.07 g, 0.21 mmol, 73%. Elemental Anal. Calc.
for 7 C18H N O Cu: C, 51.98; H, 3.88; N, 13.47, Cu, 15.28. Found:
16 4 4
We thank the Irish Government for support under its ‘Pro-
gramme for Research in Third Level Institutions’, Enterprise Ireland
(
International Collaboration Programme) and EU COST D21 for
C, 51.60; H, 3.57; N, 13.00; Cu, 15.16%. IR (KBr disc): 3500–
support. EF thanks TÁMOP 4.2.1./B-09/1/KONV-2010-0007 for
support.
ꢂ1
3
2
200w, 1615vs, 1571vs, 1531vs, 1466s, 1258vs, 1119s cm . After
months standing at room temperature the filtrate above pro-
duced a very small amount of pale green crystalline material of
Cu(Cha)H O(Cl), 8, suitable for X-ray analysis.
Appendix A. Supplementary material
2
4
.2.7. [Zn(Cha)
To a solution of Zn(OAc)
was added a solution of 2 (0.1 g, 0.60 mmol) in hot ethanol
2
]ꢁ2H
2
O, (9)
CCDC760839–760844 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(0.05 g. 0.27 mmol) in water (3 cm3)
2
3
(
20 cm ). The reaction mixture was left to stand at room tempera-
ture for 7 days during which colourless crystals of 9 suitable for X-
ray structure analysis were obtained. These were collected by fil-
tration and washed with ethanol. Yield: 0.08 g, 0.17 mmol, 62%.
References
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H
22
N
4
O
6
Zn: C, 49.96; H, 4.82; N,
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1
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