Di-, tri-, and tetranuclear zinc hydroxamate complexes as structural models for the inhibition of zinc hydrolases by hydroxamic acids

Article abstract of DOI:10.1021/ic050849m

Attempts to produce Zn analogues of the structural model complexes [M ₂(μ-O₂CR)₂(O₂CR) ₂(μ-H₂O)(tmen)₂] (M = Ni, Co, Mn; R = CH₃, C(CH₃)₃, CF₃) by the reaction of a series of zinc carboxylates with N,N,N′,N′- tetramethylethylenediamine (tmen), resulted in the mononuclear complexes [Zn(OAc)₂(tmen)] (1) and [Zn(crot)₂-(tmen)]·0. 5H₂O (2) for R = CH₃ and (CH)₂CH₃, respectively, and the dinuclear complexes [Zn₂(μ-piv) ₂(piv)₂(μ-H₂O)(tmen)₂] (3) and [Zn₂(μ-OAc_F)₂(OAc_F) ₂(μ-H₂O)(tmen)₂] (4) for R = C(CH ₃)₃ and CF₃, respectively. In contrast to the analogous imidazole series, i.e., [M₂(μ-O₂CR) ₂(O₂CR)₂(μ-H₂O)(Im)₄] (M = Ni, Co, Mn; R = CH₃, C(CH₃)₃, CF ₃), zinc carboxylates react with imidazole to give only the mononuclear complexes [Zn(OAc)₂(Im)₂] (5), [Zn-(crot) ₂(Im)₂]·H₂O (6), [Zn(piv) ₂(Im)₂]·0.5H₂O (7), and [Zn(OAc _F)₂(Im)₂] (8). Reaction of 1, 2, and 3 with either acetohydroxamic acid (AHA) or benzohydroxamic acid (BHA) gives the dinuclear complexes [Zn₂(O₂CR)₃(R′A)- (tmen)], where R′A = acetohydroxamate (AA) (9, 10, 11) or benzohydroxamate (BA) (13, 14, 15). In these complexes, the zinc atoms are bridged by a single hydroxamate and two carboxylates, with a capping tmen ligand on one zinc and a monodentate carboxylate bonded to the second zinc atom. This composition models closely the observed structure of the active site of the p-iodo-D-phenylalanine hydroxamic acid inhibited Aeromonas proteolytica aminopeptidase enzyme. In contrast, 4 reacts with AHA to give [Zn₂(OAc_F) ₃(tmen)₂(AA)] (12) with an additional tmen ligand so that both Zn atoms are 6-coordinate, whereas reaction with BHA gives the trinuclear complex [Zn₃(OAc_F)₄(tmen)₂(BA) ₂] (16). Reactions of 3 and 4 with glutarodihydroxamic acid (GluH₂A₂) produce the tetranuclear complexes [Zn ₄(piv)₆(tmen)₄(GluA₂)] (18) and [Zn₄(OAc_F)₆(tmen)₄(GluA ₂)] (19).

Full text of DOI:10.1021/ic050849m

Inorg. Chem. 2006, 45, 4497−4507
Di-, Tri-, and Tetranuclear Zinc Hydroxamate Complexes as Structural
Models for the Inhibition of Zinc Hydrolases by Hydroxamic Acids
David A. Brown, Noel J. Fitzpatrick,* Helge Mu1ller-Bunz, and AÄ ine T. Ryan
School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology,
Conway Institute of Biomolecular and Biomedical Research, UniVersity College Dublin,
Belfield, Dublin 4, Ireland
Received May 25, 2005
Attempts to produce Zn analogues of the structural model complexes [M2(
Ni, Co, Mn; R CH3, C(CH3)3, CF3) by the reaction of a series of zinc carboxylates with N,N,N
tetramethylethylenediamine (tmen), resulted in the mononuclear complexes [Zn(OAc)2(tmen)] (1) and [Zn(crot)2-
(tmen)] 0.5H2O (2) for R CH3 and (CH)2CH3, respectively, and the dinuclear complexes [Zn2( -piv)2(piv)2(
H2O)(tmen)2] (3) and [Zn2( -OAcF)2(OAcF)2( -H2O)(tmen)2] (4) for R C(CH3)3 and CF3, respectively. In contrast
to the analogous imidazole series, i.e., [M2( -O2CR)2(O2CR)2( -H2O)(Im)4] (M Ni, Co, Mn; R CH3, C(CH3)3,
CF3), zinc carboxylates react with imidazole to give only the mononuclear complexes [Zn(OAc)2(Im)2] (5), [Zn-
(crot)2(Im)2] H2O (6), [Zn(piv)2(Im)2] 0.5H2O (7), and [Zn(OAcF)2(Im)2] (8). Reaction of 1, 2, and 3 with either
acetohydroxamic acid (AHA) or benzohydroxamic acid (BHA) gives the dinuclear complexes [Zn2(O2CR)3(R A)-
(tmen)], where R acetohydroxamate (AA) (9, 10, 11) or benzohydroxamate (BA) (13, 14, 15). In these complexes,
µ
-O2CR)2(O2CR)2(
µ-H2O)(tmen)2] (M
)
)
′,N′-
‚
)
µ
µ-
µ
µ
)
µ
µ
)
)
‚
‚
′
′A )
the zinc atoms are bridged by a single hydroxamate and two carboxylates, with a capping tmen ligand on one zinc
and a monodentate carboxylate bonded to the second zinc atom. This composition models closely the observed
structure of the active site of the p-iodo-D-phenylalanine hydroxamic acid inhibited Aeromonas proteolytica
aminopeptidase enzyme. In contrast, 4 reacts with AHA to give [Zn2(OAcF)3(tmen)2(AA)] (12) with an additional
tmen ligand so that both Zn atoms are 6-coordinate, whereas reaction with BHA gives the trinuclear complex
[Zn3(OAcF)4(tmen)2(BA)2] (16). Reactions of 3 and 4 with glutarodihydroxamic acid (GluH2A2) produce the tetranuclear
complexes [Zn4(piv)6(tmen)4(GluA2)] (18) and [Zn4(OAcF)6(tmen)4(GluA2)] (19).
Introduction
form dinuclear metallohydrolases.4 Structurally, these en-
zymes contain a dinuclear metal active site featuring Zn(II),
Ni(II), Co(II), and Mn(II) bridged by carboxylates and occur,
respectively, in leucine aminopeptidase,5 urease,6 methion-
ineaminopeptidase,7 and arginase.8 Significantly, zinc hy-
drolases are involved in bacterial resistance (deactivation of
penicillin by metallo-â-lactamases) and cancer progression
(matrix metalloproteinases).2 As a result, their inhibitors are
potential antibacterial and anticancer drugs.9
Zinc is the second most abundant metal in the body, after
iron, playing catalytic, structural, regulatory, and noncatalytic
roles in enzymes and a structural role in zinc finger
proteins.1,2 With well over 300 structurally identified en-
zymes, it is the only metal found in representatives of all
six International Union of Crystallography classes of en-
zymes, namely oxidoreductases, transferases, hydrolases,
lyases, isomerases, and ligases.3 The hydrolases are respon-
sible for a large number of physiological functions and
pathologies, e.g., neoplasms, inflammations, infections. In
addition to Zn, the transition metals Ni, Co, and Mn also
Hydroxamic acids are known inhibitors of the metallo-
hydrolases.9 Recent structural developments have increased
(4) Wilcox, D. Chem. ReV. 1996, 96, 2435-2458.
(5) Stra¨ter, N.; Lipscomb, W. N. Biochemistry 1995, 34, 14792-14800.
(6) Jabri, E.; Carr, M.; Hausinger, R.; Karplus, P. Science 1995, 268, 998-
1004.
(7) Roderick, S.; Matthews, B. Biochemistry 1993, 32, 3907-3912.
(8) Kanyo, Z.; Scolnick, L.; Ash, D.; Christianson, D. Nature 1996, 383,
554-557.
(9) Muri, E. M. F.; Nieto M. J.; Sindelar R. D.; Williamson, J. S. Curr.
Med. Chem. 2002, 9, 1631-1653.
* To whom correspondence should be addressed. Telephone: +353-1-
716-2495. Fax: +353-1-716-2127. E-mail: noel.fitzpatrick@ucd.ie.
(1) Auld, D. S. BioMetals 2001, 14, 271-313.
(2) Lipscomb, W. N.; Stra¨ter, N. Chem. ReV. 1996, 96, 2375-2433.
(3) Galdes, A.; Vallee, B. L. Metal Ions in Biological Systems; Sigel, H.,
Ed.; Marcel Dekker: New York, 1983; Vol. 15, Chapter 1, p 1.
10.1021/ic050849m CCC: $33.50
Published on Web 05/02/2006
© 2006 American Chemical Society
Inorganic Chemistry, Vol. 45, No. 11, 2006 4497

Brown et al.
Figure 1. Modes of coordination of hydroxamate inhibitors to mononuclear
sites (left) and dinuclear sites (right).
our knowledge of how hydroxamic acids bind to metal
centers; however, the mechanisms are still a matter for
debate. Inhibition of mononuclear centers involves chelation
of the metal ion by the hydroxamate in the ‘O,O’ bonding
mode, i.e., through the carbonyl oxygen and through the
deprotonated hydroxyl oxygen (Figure 1). Crystal structures
of many mononuclear zinc enzymes with coordinated hy-
droxamate inhibitors have been solved, e.g., DD-carboxypep-
tidase,10 thermolysin,11 neutrophil collagenase (matrix met-
alloproteinase-8),12 fibroblast collagenase (matrix metallo-
proteinase-1),13 and fuculose-1-phosphate aldose.14 All ex-
amples show the hydroxamate chelating the metal center
through both oxygens.
Figure 2. Aeromonas proteolytica aminopeptidase inhibited by p-iodo-
D-phenylalanine hydroxamic acid.18
In dinuclear enzymes, inhibition occurs when the hydrox-
amate is coordinated so that it bridges both metal centers.
Specifically, the carbonyl oxygen coordinates to the first
metal center and the deprotonated hydroxamate oxygen
bridges both metal centers (Figure 1). This coordination mode
was initially observed in the model complex [Ni2(Hshi)(H2-
Figure 3. Model hydroxamate complex ions [M2(O2CR)(R′A)2(tmen)2]+
(left) and [M2(O2CR)(R′A)2(Im)4]+ (right).
-
shi)(pyr)4(OAc)] (OAc ) CH3CO2 ), which contains two
bridging hydroxamates.15 The crystal structures of acetohy-
droxamic acid bound to both Klebsiella aerogenes urease16
and Bacillus pasteurii urease17 show a single inhibitor
molecule bound to the enzyme in the same mode as in
[Ni2(Hshi)(H2shi)(pyr)4(OAc)]. To the best of our knowledge,
only one crystal structure of a dinuclear zinc enzyme with a
bridged coordinated hydroxamate inhibitor is known, i.e.,
Aeromonas proteolytica aminopeptidase (Zn2AAP) inhibited
by p-iodo-D-phenylalanine hydroxamic acid (Figure 2).18
The complexes [M2(µ-O2CR)2(O2CR)2(µ-H2O)(tmen)2] (M
) Ni, Co, Mn; R ) CH3, C(CH3)3, CF3; tmen ) N,N,N′,N′-
tetramethylethylenediamine) consist of a dinuclear metal
center with bridging carboxylates and a bridging water,19-23
making them ideal candidates for structurally modeling the
dinuclear metallohydrolases which also contain a dinuclear
active site bridged by the carboxylate end of an amino acid.4
We have shown that reacting the dinuclear complexes [M2(µ-
O2CR)2(O2CR)2(µ-H2O)(tmen)2] or [M2(µ-O2CR)2(O2CR)2-
(µ-H2O)(Im)4] (Im ) imidazole) with 2 equiv of hydroxamic
acid gives the hydroxamate complex [M2(O2CR)(R′A)2-
(tmen)2][O2CR] or [M2(O2CR)(R′A)2(Im)4][O2CR] (Figure
3), respectively, (M ) Ni, Co, Mn; R ) CH3, (CH3)3C; R′A
) acetohydroxamate, benzohydroxamate, N-phenylaceto-
hydroxamate).19-22 However, when R ) CF3 was used,
different complexes were produced.23 When either [Ni2(µ-
-
OAcF)2(OAcF)2(µ-H2O)(tmen)2] (OAcF ) CF3CO2 ) or [Co2-
(µ-OAcF)2(OAcF)2(µ-H2O)(tmen)2] was reacted with 2 equiv
of hydroxamic acid, a trinuclear complex of the form [M3-
(OAcF)4(tmen)2(R′A)2] was formed (Figure 4). Proton transfer
to the tmen nitrogen atoms and formation of the doubly
protonated salt, [tmenH2][OAcF]2 with H-bonding between
the protons and the trifluoroacetates, also occurred.23
(10) Charlier, P.; Dideberg, O.; Jamoulle, J. C.; Fre`re, J. M.; Ghuysen, J.
M.; Dive, G.; Lamotte-Brasseur, J. Biochem. J. 1984, 219, 763-772.
(11) Holmes, M. A.; Matthews, B. W. Biochemistry 1981, 20, 6912-6920.
(12) (a) Stams, T.; Spurlino, J. C.; Smith, D. L.; Wahl, R. C.; Ho, T. F.;
Qoronfleh, M. W.; Banks, T. M.; Rubin, B. Nature, Struct. Biol. 1994,
1, 119-123. (b) Grams, F.; Crimmin, M.; Hinnes, L.; Huxley, P.;
Pieper, M.; Tschesche, H.; Bode, W. Biochemistry 1995, 34, 14012-
14020. (c) Grams, F.; Reinemer, P.; Powers, J. C.; Kleine, T.; Pieper,
M.; Tschesche, H.; Huber, R.; Bode, W. Eur. J. Biochem. 1995, 228,
830-841.
(19) Brown, D. A.; Cuffe, L. P.; Deeg, O.; Errington, W.; Fitzpatrick, N.
J.; Glass, W. K.; Herlihy, K. Kemp, T. J., Nimir, H. Chem. Commun.
1998, 2433-2434.
(13) Spurlino, J. C.; Smallwood, A. M.; Carlton, D. D.; Banks, T. M.;
Vavra, K. J.; Johnson, J. S.; Cook, E. R.; Falvo, J.; Wahl, R. C.;
Pulvino, T. A.; Wendoloski, J. J.; Smith, D. L. Proteins 1994, 19,
98-109.
(20) Arnold, M.; Brown, D. A.; Deeg, O.; Errington, W.; Hasse, W.;
Herlihy, K.; Kemp, T. J.; Nimir, H.; Werner, R. Inorg. Chem. 1998,
37, 2920-2925.
(14) Dreyer, M. K.; Schulz, G. E. J. Mol. Biol. 1993, 231, 549-553.
(15) Stemmler, A. J.; Kampf, J. W.; Kirk, M. L.; Pecoraro, V. L. J. Am.
Chem. Soc. 1995, 117, 6368-6369.
(21) Brown, D. A.; Errington, W.; Glass, W. K.; Hasse, W.; Kemp, T. J.;
Nimir, H.; Ostrovsky, S.; Werner, R. Inorg. Chem. 2001, 40, 5962-
5971.
(16) Pearson, M.; Michel, L.; Hausinger, R.; Karplus, P. Biochemistry 1997,
36, 8164-8172.
(22) Brown, D. A.; Glass, W. K.; Fitzpatrick, N. J.; Kemp, T. J.; Errington,
W.; Clarkson, G. J.; Hasse, W.; Karsten, F.; Mahdy, A. H. Inorg.
Chim. Acta 2004, 357, 1411-1436.
(23) Brown, D. A.; Clarkson, G. J.; Fitzpatrick, N. J.; Glass, W. K.; Hussein,
A. J.; Kemp, T. J.; Mu¨ller-Bunz, H. Inorg. Chem. Commun. 2004, 7,
494-498.
(17) Benini, S.; Rypniewski, W. R.; Wilson, K. S.; Miletti, S.; Ciurli, S.;
Mangani, S. J. Biol. Inorg. Chem. 2000, 5, 110-118.
(18) Chevrier, B.; D’Orchymount, H.; Schaik, C.; Tamus C.; Moras, D.
Eur. J. Biochem. 1996, 237, 393-398.
4498 Inorganic Chemistry, Vol. 45, No. 11, 2006

Di-, Tri-, and Tetranuclear Zinc Hydroxamate Complexes
Figure 4. General structure of the trinuclear complex [M3(OAcF)4(tmen)2-
(R′A)2].
When either [M2(µ-O2CR)2(O2CR)2(µ-H2O)(tmen)2] or
[M2(µ-O2CR)2(O2CR)2(µ-H2O)(Im)4] (where M ) Ni or Co
and R ) CH3 or (CH3)3C)) was reacted with 1 equiv of
glutarodihydroxamic acid (GluH2A2), in the presence of a
counterion, the ion [M2(O2CR){µ-O(N)(OC)2(CH2)3}(tmen)2]+
was formed with the elimination of hydroxylamine.19 Inter-
estingly, when the urea complex [M2(O2CR)3(urea)(tmen)2]
was reacted with 1 equiv of GluH2A2, in the presence of a
counterion, the tetranuclear ion [M4(O2CR)2(GluA2)2(tmen)4]2+
(GluA2 ) glutarodihydroxamate) was formed.19 The complex
is composed of two dinuclear [M2(O2CR)(0.5GluA2)2-
(tmen)2]2+ units, linked by the aliphatic chains of the GluA2’s.
The general structure of each of the dinuclear units is similar
to that of the [M2(O2CR)(R′A)2(tmen)2]2+ complexes (Figure
3).19
With the exception of our preliminary communication,24
in which the crystal structures of 1 and the product of its
reaction with benzohydroxamic acid (BHA), 13, were
reported, such structures have not yet been reported for zinc
for either the dinuclear model hydrolases or the bridged
hydroxamate inhibited model hydrolases.
Figure 5. General structures of 1 (R1 ) CH3), 2 (R1 ) (CH)2CH3), 3 (R2
) C(CH3)3), 4 (R2 ) CF3), 5 (R3 ) CH3), 6 (R3 ) (CH)2CH3), 7 (R3 )
C(CH3)3), and 8 (R3 ) CF3).
distortion of the metal-ligand angles from 90°. Although
there is some asymmetry in the M-O distances, Zn1-O1
is 2.052(4) Å and Zn1-O2 is 2.353(4) Å; both acetates are
clearly bidentate chelating. The complex 2 is also distorted
octahedral with slight distortion of the metal-ligand angles
from 90°. For example, O1-Zn1-N1 is 102.32(13)° and
O2-Zn1-O2′ is 91.84(3)°. Although there is some asym-
metry in the M-O distances, Zn1-O1 is 2.069(3) Å and
Zn1-O2 is 2.299(4) Å; both crotonates are clearly bidentate
chelating. These distances are shorter than those in 1. A water
molecule is shared between two complex molecules, hydrogen-
bonded to O1 in both. The water is hydrogen-bonded to O1,
which is the more tightly bound oxygen to the metal, thus
indicating no tendency for the crotonate to become mono-
dentate with hydrogen bonding to the water, as observed in
the dinuclear complexes [M2(µ-O2CR)2(O2CR)2(µ-H2O)-
(tmen)2]. The Zn-Zn separation is 8.064 Å.
Results and Discussion
1. Structural Models for Zinc Hydrolases. The structural
model complexes [M2(µ-O2CR)2(O2CR)2(µ-H2O)(tmen)2] (M
) Ni, Co, Mn; R ) CH3, C(CH3)3, CF3) are prepared by the
reaction of the relevant metal carboxylate with tmen.19-23
However, when zinc acetate or zinc crotonate [Zn(CH3(CH)2-
CO2)] was reacted with tmen, the mononuclear complexes
124 or 2 were obtained instead (Figure 5), whereas with zinc
pivalate and zinc trifluoroacetate, the dinuclear complexes
3 and 4 were formed, with similar structures to the analogous
Ni, Co, and Mn dinuclear complexes (Figure 5). The model
complexes [M2(µ-O2CR)2(O2CR)2(µ-H2O)(Im)4] (M ) Ni,
Co, Mn; R ) CH3, C(CH3)3, CF3) also exist, prepared by
the reaction of the relevant metal carboxylate with imida-
zole.22,23 When the zinc carboxylates were reacted with
imidazole, only the mononuclear complexes 5, 6, 7, and 8
were produced (Figure 5).
1.1. X-ray Crystal Structure of the Dinuclear Complex
4. The crystal structure of 4 is shown in Figure 6 with
selected bond lengths and angles in the Supporting Informa-
tion. Both zinc atoms in 4 are octahedrally coordinated with
only very slight deviation of the metal-ligand angles from
90°. The Zn1-Zn2 distance is 3.729 Å, and the Zn1-
O1-Zn2 angle is 116.41°. The M-M distance in 4 is
significantly longer than that in the Ni and Co analogues,
which are 3.676 and 3.702 Å, respectively.23 The bond angles
in 4 are quite similar to those in [Co2(µ-OAcF)2(OAcF)2(µ-
H2O)(tmen)2].23 The hydrogen bonds from the bridging water
to the monodentate trifluoroacetates are unsymmetrical in 4
at (O1)H20‚‚‚O7 1.79(3) and (O1)H10‚‚‚O9 1.76(3) Å.
Significantly, for the zinc complex, the average Zn-O bond
length is 2.115 Å, much longer than 2.084 and 2.092 Å in
the Ni and Co dinuclear complexes, respectively, reflecting
how weakly the zinc dinuclear complex is held together.
Crystallographic data for 2, 4, and 6-8 are given in Table
1 with selected bond lengths and angles and ORTEP figures
given in the Supporting Information. The previously re-
ported24 complex 1 is distorted octahedral with slight
1.2. Mononuclear Compounds 6-8. Crystallographic
data for the three mononuclear complexes 6-8 can be found
in Table 1 with selected bond lengths and angles and ORTEP
diagrams given in the Supporting Information. Complex 5
(24) Brown, D. A.; Errington, W.; Fitzpatrick, N. J.; Glass, W. K.; Kemp,
T. J.; Nimir, H.; Ryan, A. T. Chem. Commun. 2002, 1210-1211.
Inorganic Chemistry, Vol. 45, No. 11, 2006 4499

Brown et al.
4500 Inorganic Chemistry, Vol. 45, No. 11, 2006

Di-, Tri-, and Tetranuclear Zinc Hydroxamate Complexes
Figure 7. General structures of complexes 9-11 and 13-15. Key: 9 (R1
) CH3, R2 ) CH3), 10 (R1 ) (CH)2CH3, R2 ) CH3), 11 (R1 ) C(CH3)3,
R2 ) CH3), 13 (R1 ) CH3, R2 ) C6H5), 14 (R1 ) (CH)2CH3, R2 ) C6H5),
15 (R1 ) C(CH3)3, R2 ) C6H5).
of the monodentate carboxylate is hydrogen-bonded to the
NH group of the acetohydroxamate. This zinc hydroxamate
model complex, [Zn2(O2CR)3(tmen)(R′A)], shares many
important structural features with p-iodo-D-phenylalanine
hydroxamic acid inhibited Aeromonas proteolytica ami-
nopeptidase.18 Both are dinuclear, with a bidentate bridging
carboxylate (aspartate in the enzyme) and a bridging hy-
droxamate. Significantly, they both share a similarity between
the hydrogen bonding from the monodentate acetate to the
NH of the hydroxamate in the model complex and the
hydrogen bonding from the monodentate Glu151 in the
enzyme. In all reactions with BHA, the side product [Zn-
(BA)2]‚H2O (BA ) benzohydroxamate) is produced, which
is amorphous, highly insoluble, and probably polymeric.
2.2. Reactions of the Dinuclear Complexes 3 and 4 with
AHA and BHA. Given that 3 and 4 have structures
analogous to the Ni, Co, and Mn model dinuclear complexes,
it was expected that, on reaction with AHA and BHA, the
bis-hydroxamate-bridged dinuclear complex [Zn2(piv)(tmen)2-
(R′A)2][piv] (piv ) (CH3)3CCO2-)22 and the trinuclear [Zn3-
(OAcF)4(tmen)2(R′A)2]23 would form, analogous to those
formed with Ni, Co, and Mn. However, the reactions of 3
with both AHA and BHA gave a product of general formula
[Zn2(O2CR)3(tmen)(R′A)], i.e., 11 and 15 (Figure 7), both
of which are analogous in structure to complexes 9, 10, 13,
and 14. When 4 was reacted with AHA, instead of producing
the expected [Zn3(OAcF)4(tmen)2(AA)2] (AA ) acetohy-
droxamate), the dinuclear complex 12 (Figure 8) was formed.
This complex is analogous in structure to complexes 9-11
and 13-15 except that in this case there are two tmen
ligands. Consequently, both of the zinc atoms are six-
coordinate.
Figure 6. X-ray crystal structure of 4.
is distorted tetrahedral25 and in contrast to 1, where the
acetates are bidentate chelating, in 5 they are clearly
monodentate. Like 5, complex 6 is distorted tetrahedral with
slight distortion of the metal-ligand angles from 109°. Both
crotonates are clearly monodentate with bond lengths of
Zn1-O1 ) 1.988(14) Å, Zn1-O2 ) 2.645(2) Å, Zn1-O3
) 1.973(15) Å, Zn1-O4 ) 2.921(2) Å. The bonded Zn-O
distances are only slightly different from those in 5, which
are 1.964 and 1.990 Å. The structure of 6 also contains a
water molecule and extensive hydrogen bonding. Complexes
7 and 8 are also distorted tetrahedral with monodentate
carboxylates. Tables of bond lengths and angles are available
in the Supporting Information.
2. Structural Models for Hydroxamate Inhibition of
Zinc Hydrolases. The dinuclear hydrolase structural models
[M2(µ-O2CR)2(O2CR)2(µ-H2O)(tmen)2] (M ) Ni, Co, Mn;
R ) CH3, C(CH3)3), react with hydroxamic acids to give
the hydroxamate bridged complexes [M2(µ-O2CR)(R′A)2-
(tmen)2][O2CR], which closely model the inhibited hydro-
lases, e.g., urease. In view of this, the reactions of the
aforementioned zinc complexes with hydroxamic acids were
studied and the resulting complexes compared to hydrox-
amate inhibited zinc hydrolases, such as those involved in
cancer progression and antibiotic resistance.
2.1. Reactions of the Mononuclear Complexes 1 and 2
with Acetohydroxamic Acid (AHA) and BHA. The reac-
tions of the mononuclear zinc complexes 1 and 2 with AHA
and BHA did not produce hydroxamate dibridged complexes
analogous to [M2(µ-O2CR)2(O2CR)2(µ-H2O)(tmen)2] (M )
Ni, Co, Mn; R ) CH3, C(CH3)3). Instead, neutral dinuclear
complexes of general formula [Zn2(O2CR)3(tmen)(R′A)] were
formed, i.e., 9, 10, 13,24 and 14 (Figure 7), in which the two
zinc ions are bridged by a single hydroxamate and by two
bridging bidentate carboxylates. The first zinc ion has a
coordination number of six, with a capping tmen ligand, and
the second zinc ion has a coordination number of four, and
instead of a tmen ligand, there is a monodentate carboxylate
bound. Hence, the introduction of a hydroxamic acid has
induced dinuclearity in the complex. The ‘dangling’ oxygen
The reaction of 4 with BHA produced the trinuclear
complex 16 (Figure 8) as expected, with proton transfer to
the nitrogen atoms of excess tmen and formation of the
doubly protonated salt, [tmenH2][OAcF]2.23 This is the only
reaction of the zinc model complexes with hydroxamic acids,
which produces exactly the same result as the analogous Ni
and Co reactions. The proposed mechanism for the formation
of the trinuclear complex 16 is as follows. The dinuclear
complex 4 reacts with 2 equiv of BHA to form the
bis-benzohydroxamate chelate [Zn(BA)2]‚H2O, with the
transfer of the hydroxamic protons to tmen to form [tmenH2]-
[OAcF]2 (Step A). One equivalent of [Zn(BA)2]‚H2O then
(25) (a) Chen, X.-M.; Xu, Z.-T.; Huang, X.-C. J. Chem. Soc., Dalton Trans.
1994, 2331-2332. (b) Chen, X.-M.; Ye, B.-H.; Huang, X.-C.; Xu,
Z.-T. J. Chem. Soc., Dalton Trans. 1996, 3465-3468.
Inorganic Chemistry, Vol. 45, No. 11, 2006 4501

Brown et al.
Figure 8. General structure of complexes 12 and 16.
a different structure to the tetranuclear ion [M4(O2CR)2-
(GluA2)2(tmen)4]2+, which was formed from the reaction of
the urea complex [M2(O2CR)3(urea)(tmen)2] with GluH2A2
(M ) Ni, Co).20
2.5. Reactions with N-Methylbenzohydroxamic Acid
(NMeBHA) and N-Phenylbenzohydroxamic Acid (NPh-
BHA). The hydrogen bonding between the NH of the
hydroxamate ligand and the dangling oxygen of the mono-
dentate carboxylate in the complexes 9-15, 18, and 19 has
not been observed previously in the analogous Ni, Co, Mn
complexes. To test the importance of this hydrogen bond in
the formation of dinuclear zinc hydroxamate complexes, the
model hydrolases 1-4 were reacted with the N-substituted
hydroxamic acids, NMeBHA and NPhBHA, thus eliminating
the availability of the NH proton. If dinuclear complexes
were produced, then it may be concluded that the H-bonding
between the hydroxamate NH and monodentate carboxylate
is not a factor in dinuclear complex formation. However,
when 1-4 were reacted with the N-substituted hydroxamic
acids, all of the hydroxamic acid was converted into [Zn-
(R′A)2] and the remaining unreacted model hydrolase was
recovered. Both [Zn(NMeBA)2] (NMeBA ) N-methylben-
zohydroxamate) and [Zn(NPhBA)2] (NPhBA ) N-phenyl-
benzohydroxamate) are highly insoluble, amorphous, and
most likely polymeric, similar to [Zn(BA)2]‚H2O. It is
important to note that the reaction of [M2(µ-O2CR)2(O2CR)2-
(µ-H2O)(tmen)2] (M ) Ni, Co; R ) CH3, C(CH3)3) with
N-phenylacetohydroxamic acid does produce the dinuclear
complex [M2(O2CR)(NPhAA)2(tmen)2]+ (NPhAA ) N-
phenylacetohydroxamate),22 thus suggesting that the presence
of the NH proton and the hydrogen bond is only important
when M ) Zn.
Figure 9. Structure of the mononuclear complex 17.
reacts with the remaining 4 to form the trinuclear complex
16.
Step A: 2 equiv 4 + 4BHA f
2[Zn(BA)2]‚H2O + 2[tmenH2][OAcF]2 + 4
Step B: 4 + [Zn(BA)2]‚H2O f 16
Overall Reaction: 2 equiv 4 + 4BHA f
2[Zn(BA)2]‚H2O + 2[tmenH2][OAcF]2 + 16
2.3. Reaction of Imidazole Complex 8 with BHA. In
contrast to the reaction of [M2(µ-O2CR)2(O2CR)2(µ-H2O)-
(Im)4] with hydroxamic acid to give the hydroxamate
complex [M2(O2CR)(R′A)2(Im)4][O2CR] (M ) Ni, Co,
Mn),22 the reaction of the mononuclear imidazole complex
8 with BHA gave the mononuclear complex 17 (Figure 9).
The complex is five-coordinate with distorted trigonal
bipyramidal geometry around zinc. The benzohydroxamate
is bidentate chelating in the ‘O,O’ mode, i.e., through the
carbonyl oxygen and through the deprotonated hydroxamate
OH. The mononuclear complex 17 is stoichiometrically half
of the expected dinuclear complex [Zn2(OAcF)(BA)2(Im)4]-
[OAcF]. It is possible that the dinuclear complex formed first
but then partially dissociated to the more stable neutral
mononuclear complex 17. The model complex bears a close
similarity to the structure of thermolysin inhibited by L-Leu-
NHOH hydroxamic acid.11
2.6. Dinuclear Complexes 9-11. Crystallographic data
for complexes 9-11 are shown in Table 2. Selected bond
2.4. Reactions with GluH2A2. When [M2(µ-O2CR)2(O2-
CR)2(µ-H2O)(tmen)2] (M ) Ni, Co and R ) CH3, C(CH3)3)
is reacted with 1 equiv of GluH2A2, in the presence of a
counterion, the ion [M2(O2CR){µ-O(N)(OC)2(CH2)3}(tmen)2]+
is formed, with elimination of hydroxylamine.20 However,
there is no reaction between either 1 or 2 with GluH2A2,
and the reactions of 3 and 4 with GluH2A2 produce a
tetranuclear complex of general formula [Zn4(O2CR)6(tmen)4-
(GluA2)], i.e., 18 and 19 (Figure 10). These complexes have
Figure 10. General structure of 18 (R ) C(CH3)3) and 19 (R ) CF3).
4502 Inorganic Chemistry, Vol. 45, No. 11, 2006

Di-, Tri-, and Tetranuclear Zinc Hydroxamate Complexes
Table 2. Crystal Data and Structure Refinement for Compounds 9-12, 16, 17, and 19
9
10
11
12
empirical formula
molecular formula
fw
C28H60N6O17Zn4
C14H29N3O8Zn4‚xH2O
1014.30
C20H35N3O8Zn2
C23H47N3O8Zn2
C20H36N5O8F9Zn2
576.25
624.38
776.28
T, K
λ
cryst syst
space group
a, Å
b, Å
c, Å
293(2)
0.71073
100(2)
0.71073
triclinic
100(2)
0.71073
293(2)
0.71073
monoclinic
C2/c (no. 15)
27.093(4)
9.8118(16)
16.806(3)
90
91.261(3)
90
4466.3(13)
4
1.508
2.191
2104
2.00 × 1.00 × 0.50
1.50-28.31
-35 e h e 35
-12 e k e 12
-22 e l e 22
36 569
monoclinic
P21/n (no. 14)
9.0134(6)
15.8999(11)
21.8147(15)
90
100.240(1)
90
3076.5(4)
4
1.348
1.603
1320
0.80 × 0.60 × 0.05
1.90-28.51
-12 e h e 12
-21 e k e 21
-28 e l e 29
51 471
monoclinic
P21/c (no. 14)
12.9946(9)
16.0297(12)
15.7070(11)
90
98.6990(10)
90
3234.1(4)
4
1.594
1.582
1584
0.40 × 0.30 × 0.30
1.83-25.00
-15 e h e 15
-19 e k e 19
-18 e l e 18
22 803
P1h (no. 2)
11.3637(8)
16.1153(11)
16.2312(11)
108.9900(10)
104.8370(10)
99.1990(10)
2619.0(3)
4
1.461
1.877
1200
0.70 × 0.50 × 0.40
1.92-28.51
-14 e h e 15
-21 e k e 21
-21 e l e 21
22 466
R, °
â, °
γ, °
V, Å3
Z
F
calc, Mg/m3
µ, mm-1
F(000)
cryst size, mm3
θ range, °
hkl ranges
reflns collected
independent reflns
R(int)
5336
0.0319
11 758
0.0152
7412
0.0315
5702
0.0263
completeness to æ max
96.0%
88.3%
94.8%
99.9%
max. and min. transmission 0.4071 and 0.0968
0.5206 and 0.3533
11 758/0/619
1.045
0.9241 and 0.3603
7412/0/513
1.055
0.6482 and 0.5702
5702/0/494
1.032
data/restraints/params
5336/0/366
1.042
GOF on F2
final R indices [I > 2σ (I)]
R indices (all data)
largest diff. peak
and hole, e Å-3
R1 ) 0.0277, wR2 ) 0.0702 R1 ) 0.0406, wR2 ) 0.1050 R1 ) 0.0254, wR2 ) 0.0640 R1 ) 0.0343, wR2 ) 0.0870
R1 ) 0.0357, wR2 ) 0.0732 R1 ) 0.0451, wR2 ) 0.1079 R1 ) 0.0288, wR2 ) 0.0659 R1 ) 0.0434, wR2 ) 0.0930
0.477, -0.297
2.426, -1.231
0.547, -0.323
0.521, -0.281
16
17
19
empirical formula
C38H54N6O13F12Zn3
C15H14N5O4F3Zn
C41H72N10O16F18Zn4
molecular formula
fw
T, K
λ
cryst syst
space group
a, Å
b, Å
c, Å
1226.98
100(2)
450.68
100(2)
0.71073
1564.57
100(2)
0.71073
triclinic
P1h (no. 2)
10.6896(14)
17.774(2)
18.031(2)
65.562(2)
83.930(2)
88.327(2)
3101.1(7)
2
1.676
1.651
1596
0.20 × 0.20 × 0.05
1.26-23.00
-11 e h e 11
-19 e k e 19
-19 e l e 19
18 516
0.71073
monoclinic
P21/n (no. 14)
12.214(3)
32.725(7)
12.878(3)
90
92.736(3)
90
5141.5(19)
4
1.585
1.494
2504
1.00 × 0.90 × 0.60
2.33-27.00
-15 e h e 15
-41 e k e 41
-16 e l e 16
39 493
monoclinic
P21 (no. 4)
10.2243(6)
7.9968(5)
11.1919(7)
90
97.290(1)
90
907.67(10)
2
1.649
1.415
456
0.40 × 0.40 × 0.10
1.83-28.53
-13 e h e 13
-10 e k e 10
-14 e l e 14
15 513
R, °
â, °
γ, °
V, Å3
Z
F
calc, Mg/m3
µ, mm-1
F(000)
cryst size, mm3
θ range, °
hkl ranges
reflns collected
independent reflns
R(int)
11 164
0.0449
4231
0.0239
8551
0.0356
completeness to æ max
99.5%
94.3%
99.1%
max. and min. transmission 0.4675 and 0.3165
0.8714 and 0.7407
4231/1/257
1.046
0.9220 and 0.7181
8551/0/826
1.089
data/restraints/params
11 164/0/740
1.166
GOF on F2
final R indices [I > 2σ (I)]
R indices (all data)
largest diff. peak
and hole, e Å-3
R1 ) 0.0639, wR2 ) 0.1366 R1 ) 0.0319, wR2 ) 0.0808 R1 ) 0.0448, wR2 ) 0.1150
R1 ) 0.0744, wR2 ) 0.1408 R1 ) 0.0326, wR2 ) 0.0813 R1 ) 0.0634, wR2 ) 0.1245
1.070, -1.059
1.441, -0.255
1.011, -0.653
lengths and angles and figures are contained in the Support-
previously reported,24 and crystals of 14 and 15 were not
ing Information. The crystal structure of 13 has been
suitable for X-ray crystallographic analysis. The X-ray crystal
Inorganic Chemistry, Vol. 45, No. 11, 2006 4503

Brown et al.
Figure 11. X-ray crystal structure of 12. Hydrogens are omitted for clarity.
Figure 12. X-ray crystal structure of 16.
structures of 9-11 reveal dinuclear complexes where Zn1
is four-coordinate and Zn2 is six-coordinate and thus
analogous in structure to the previously reported 13,24 except
that in these cases, acetohydroxamate is in place of benzo-
hydroxamate.
Å. There are two capping tmen ligands, one each on Zn2
(Zn2-N3 ) Zn2-N4 ) 2.168(3) Å) and Zn3 (Zn3-N5 )
2.164(4) Å, Zn3-N6 ) 2.162(4) Å). Bridging Zn1 and Zn2
are two bidentate bridging trifluoroacetates (Zn1-O5 )
2.167(3) Å, Zn1-O7 ) 2.079(3) Å, Zn2-O6 ) 2.180(3)
Å, Zn2-O8 ) 2.113(3) Å, O5-C27-O6 ) 131.3(4)°,
O7-C29-O8 ) 130.9(4)°). A second pair of bidentate
bridging trifluoroacetates bridge Zn1 and Zn3 (Zn1-O9 )
2.147(3) Å, Zn1-O11 ) 2.062(3) Å, Zn3-O10 ) 2.166(3)
Å, Zn3-O12 ) 2.094(3) Å, O9-C31-O10 ) 130.9(4)°,
O11-C33-O12 ) 131.2(4)°). Also bridging Zn1 and Zn2
is a benzohydroxamate, coordinated in the bridging mode
as previously observed. The carbonyl oxygen, O2, coordi-
nates to Zn2 (O2-Zn2 ) 2.083(3) Å) and the hydroxamate
oxygen, O1, bridges the two zinc atoms (O1-Zn2 ) 2.081-
(3) Å, O1-Zn1 ) 2.057(3) Å). The bridging angle Zn1-
O1-Zn2 is 115.78(14)°. A second benzohydroxamate bridges
Zn1 and Zn3. The carbonyl oxygen, O4, coordinates to Zn3
(O4-Zn3 ) 2.120(3) Å), and the hydroxamate oxygen, O3,
bridges the two zinc atoms (O3-Zn3 ) 2.068(3) Å, O3-
Zn1 ) 2.074(3) Å). The bridging angle Zn1-O3-Zn3 is
116.58(13)°. The complex is clearly unsymmetrical. There
are no monodentate trifluoroacetates as observed in previous
complexes. The distances O5‚‚‚H(N2) ) 2.098(5) Å and O9‚
‚‚H(N1) ) 2.195(5) Å indicate that some interaction may
exist between the NH of the hydroxamates and the bridging
bidentate trifluoroacetates.
2.9. X-ray Crystal Structure of the Mononuclear
Complex 17. The X-ray crystal structure of 17 (Figure 13)
reveals that the complex is mononuclear with distorted
trigonal bipyramidal geometry around the zinc. The zinc-
bonded oxygen of the monodentate trifluoroacetate, O3, and
the carbonyl oxygen of the hydroxamate, O2, are the axial
atoms with an angle O2-Zn1-O3 ) 163.33(7)°. The two
zinc-bound nitrogens of the imidazoles, N2 and N4, and the
hydroxamate oxygen, O1, are equatorial with angles N2-
Zn1-N4 ) 104.92(8)°, O1-Zn1-N2 ) 113.17(8)°, and
O2-Zn1-N4 ) 93.20(8)°. The trifluoroacetate is bound
to zinc in a monodentate fashion with Zn-O distances of
Zn1-O3 ) 2.108(17) Å and Zn1-O4 ) 3.103(2) Å. The
hydroxamate is in bidentate chelating ‘O,O’ mode with
Zn-O distances of Zn1-O1 ) 1.988(17) Å and Zn1-O2
2.7. X-ray Crystal Structure of 12. The X-ray crystal
structure of 12 (Figure 11) reveals that it is similar to the
structures of the previously described complexes 9-11 and
13-15, i.e., it is dinuclear, with two bidentate bridging
trifluoroacetates and one bridging hydroxamate, the NH of
which is hydrogen bonded to a monodentate trifluoroacetate
on Zn2. However, in this case, there are two tmen ligands,
one on each zinc atom. Therefore, the coordination environ-
ment of both zinc atoms is distorted octahedral, with angles
O2-Zn1-N3 ) 91.71(11)°, O3-Zn1-O5 ) 89.61(10)°,
N2-Zn1-O3 ) 89.69(9)°, O4-Zn2-O6 ) 91.80(10)°,
O1-Zn2-O4 ) 90.62(8)°, and N4-Zn2-O7 ) 90.16-
(9)°. The hydroxamate is coordinated in the bridging mode.
The carbonyl oxygen, O2, coordinates to Zn1 (O2-Zn1 )
2.050(2) Å) and the hydroxamate oxygen, O1, bridges the
two zinc atoms (O1-Zn1 ) 2.106(18), O1-Zn2 ) 2.075-
(17) Å). This is an asymmetric bridge, across a Zn-Zn
separation of 3.609(1) Å. The bridging angle Zn1-O1-
Zn2 is 119.33(8)°. The two metal centers are also bridged
by two bidentate bridging trifluoroacetates, with bond lengths
Zn1-O3 ) 2.175(2) Å, Zn1-O5 ) 2.056(2) Å, Zn2-O4
) 2.094(2) Å, and Zn2-O6 ) 2.149(2) Å and angles O3-
C15-O4 ) 131.4(3)° and O5-C17-O6 ) 130.20(3)°. A
third trifluoroacetate is coordinated monodentate to Zn2
(Zn2-O7 ) 2.127(2) Å, Zn2-O8 ) 3.832(5) Å). The
noncoordinated or ‘dangling’ oxygen, O8, is hydrogen
bonded to the NH of the hydroxamate (O8‚‚‚H(N1) ) 2.032-
(4) Å). Finally, there is a capping tmen on Zn1 (Zn1-N2 )
2.195(2) Å, Zn1-N3 ) 2.232(3) Å) and on Zn2 (Zn2-N4
) 2.211(3) Å, Zn2-N5 ) 2.241(2) Å). Selected bond
lengths and angles can be found in the Supporting Informa-
tion.
2.8. X-ray Crystal Structure of the Trinuclear Complex
16. The X-ray crystal structure of 16 (Figure 12) reveals that
the complex is trinuclear and approximately linear ( Zn2-
Zn1-Zn3 ) 169.31(2)°), where Zn1 is the central metal
atom. The Zn-Zn separations are as follows. Zn1-Zn2 )
3.505(2) Å, Zn1-Zn3 ) 3.524(2) Å, and Zn2-Zn3 ) 6.999
4504 Inorganic Chemistry, Vol. 45, No. 11, 2006

Di-, Tri-, and Tetranuclear Zinc Hydroxamate Complexes
Zn3 and Zn4 (Zn3-O11 ) 2.164(4) Å, Zn3-O13 ) 2.082-
(4) Å, Zn4-O12 ) 2.096(4) Å, Zn4-O14 ) 2.153(4) Å,
O11-C35-O12 ) 130.9(5)°, O13-C37-O14 ) 129.4-
(5)°). One hydroxamate end of the GluA2 bridges Zn1 and
Zn2, and the other bridges Zn3 and Zn4, both coordinated
in the bridging mode as previously observed. The carbonyl
oxygen of the first end of the hydroxamate, O2, coordinates
to Zn2 (O2-Zn2 ) 2.073(4) Å) and the hydroxamate
oxygen, O1, bridges the two zinc atoms (O1-Zn1 ) 2.097-
(4) Å, O1-Zn2 ) 2.131(4) Å). The bridging angle Zn1-
O1-Zn2 is 117.23(17)°. The carbonyl oxygen of the second
end of the hydroxamate, O10, coordinates to Zn3 (O10-
Zn3 ) 2.083(4) Å) and the hydroxamate oxygen, O9, bridges
the two zinc atoms (O9-Zn3 ) 2.111(3) Å, O9-Zn4 )
2.069(4) Å). The bridging angle Zn3-O9-Zn4 is 118.93-
(17)°. The complex is clearly unsymmetrical. There is one
trifluoroacetate coordinated in a monodentate fashion on each
of Zn1 (Zn1-O7 ) 2.143(4) Å, Zn1-O8 ) 3.798(6) Å)
and Zn4 (Zn4-O15 ) 2.130(4) Å, Zn4-O16 ) 3.741(5)
Å). Once again, the ‘dangling’ oxygens form a hydrogen
bond to the NH of the hydroxamate (O8‚‚‚H(N1) ) 1.827-
(6) Å and O16‚‚‚H(N6) ) 2.023(6) Å). Finally, there are
four capping tmen ligands, one on each on Zn1 (Zn1-N2
) 2.238(5) Å, Zn1-N3 ) 2.240(5) Å), Zn2 (Zn2-N4 )
2.217(5) Å, Zn2-N5 ) 2.197(5) Å), Zn3 (Zn3-N7 ) 2.179-
(4) Å, Zn3-N8 ) 2.241(5) Å), and Zn4 (Zn4-N9 ) 2.231-
(4) Å, Zn4-N10 ) 2.236(4) Å).
Figure 13. X-ray crystal structure of 17.
Figure 14. X-ray crystal structure of 19.
2.11. IR Spectroscopic Studies. A full list of IR peaks
and assignments for all compounds studied is contained in
the Supporting Information. The assignments for the bands
observed in the IR spectra are based on both reported values
for the zinc carboxylates26-32 and our previous work.19-24
) 2.189(17) Å. The Zn-N distances to the imidazoles are
Zn1-N2 ) 2.021(2) Å and Zn1-N4 ) 2.002(2) Å.
Individual units of 17 are linked to one another by three
hydrogen bonds, O1‚‚‚H(N5) ) 1.852 Å, O2‚‚‚H(N3) )
1.887 Å, and O4‚‚‚H(N1) ) 2.086(4) Å.
Experimental Section
2.10. X-ray Crystal Structure of the Tetranuclear
Complex 19. The X-ray crystal structure of 19 (Figure 14)
reveals that the complex is tetranuclear and is composed of
two dinuclear [Zn2(OAcF)3(tmen)2(GluA2)0.5] units linked by
the aliphatic chain of the GluA2. GluH2A2 is a dihydroxamic
acid with two hydroxamate functionalities linked by a
-(CH2)3- chain. The Zn-Zn separations in 19 are Zn1-
Zn2 ) 3.609(4) Å and Zn3-Zn4 ) 3.600(3) Å. There is a
separation of 8.741(3) Å between Zn1 and Zn3 and of 8.39-
(1) Å between Zn2 and Zn4. Selected dihedral angles are
Zn1-Zn2-Zn4-Zn3 ) 93.13(2)° and Zn2-Zn1-Zn3-
Zn4 ) 91.66(2)°. The general structure of each of the
dinuclear units is similar to that of 12, with the two zinc
atoms bridged by two bidentate bridging trifluoroacetates and
one hydroxamate, two capping tmen ligands and a mono-
dentate trifluoroacetate with hydrogen bonding to the NH
of the hydroxamate. All four zinc atoms are in a distorted
octahedral environment with selected angles as follows.
O3-Zn1-O5 ) 95.03(15)°, O1-Zn2-O4 ) 92.66(14)°,
N7-Zn3-O10 ) 93.94(16)°, and O12-Zn4-O15 )
92.53(14)°. Bridging Zn1 and Zn2 are two bidentate bridging
trifluoroacetates (Zn1-O3 ) 2.084(4) Å, Zn1-O5 ) 2.127-
(4) Å, Zn2-O4 ) 2.131(4) Å, Zn2-O6 ) 2.078(4) Å,
O3-C15-O4 ) 131.6(5)°, O5-C17-O6 ) 131.0(5)°).
A second pair of bidentate bridging trifluoroacetates bridge
Reagents and solvents were used as obtained from Sigma-
Aldrich, UK, without further purification unless otherwise stated.
The microanalytical laboratory, Chemical Services Unit, University
College Dublin, performed elemental analyses. Infrared spectra were
recorded in the solid state using 1-2% KBr disks and solutions in
a calcium fluoride cell, path length 0.1 mm, using a Perkin-Elmer
FT-IR Paragon 1000 or a Perkin-Elmer Spectrum One FT-IR
spectrometer.
Preparation of Zinc Pivalate, Zn(piv)2 and Zinc Crotonate,
Zn(crot)2‚H2O. A solution of the relevant carboxylic acid (100
mmol) in methanol was added slowly dropwise to a stirred
suspension of zinc carbonate, 2ZnCO3‚3Zn(OH)2 (10 mmol) in very
hot water, taking care to vent carbon dioxide. The reaction mixture
was allowed to stir for 48 h, after which it was filtered and the
(26) Johnson, M. K.; Powell, D. B.; Cannon, R. D. Spectrochim. Acta 1981,
37A, 899-904.
(27) Ishioka, T.; Shibata, Y.; Takahashi, M.; Kanesaka, I.; Kitagawa, Y.;
Nakamura, K. T. Spectrochim. Acta, Part A 1998, 54, 1827-1836.
(28) Clegg, W.; Little, I. R.; Straughan, B. P. Acta Crystallogr. 1986, C42,
1701-1703.
(29) Ishioka, T.; Shibata, Y.; Takahashi, M.; Kanesaka, I. Spectrochim.
Acta, Part A 1998, 54, 1811-1818.
(30) Clegg, W.; Little, I. R.; Straughan, B. P. Acta Crystallogr. 1986, C42,
919-920.
(31) Clegg, W.; Harbron, D. R.; Homan, C. D.; Hunt, P. A.; Little, I. R.;
Straughan, B. P. Inorg. Chim. Acta 1991, 186, 51-60.
(32) Mehrotra, R. C.; Bohra, R. Metal Carboxylates; Academic Press:
London, 1983.
Inorganic Chemistry, Vol. 45, No. 11, 2006 4505

Brown et al.
filtrate left to stand in air for ∼1 week to afford white Zn(piv)2
[Yield: 8.2 g (61%). Anal. Calcd for C10H18O4Zn: C, 44.88; H,
6.78; Zn, 24.43. Found: C, 44.71; H, 6.72; Zn, 24.30] or Zn(crot)2‚
H2O [Yield: 18.5 g (73%). Anal. Calcd for C32H42O18Zn5: C, 36.90;
H, 4.06; Zn, 31.39. Found: C, 36.80; H, 3.95; Zn, 30.03].
to stand in air to produce colorless crystals of 13, 14, 15, and 16,
respectively. Yield of 13: 0.8 g (14.3%). Anal. Calcd for
C19H31N3O8Zn2 (13): C, 40.73; H, 5.58; N, 7.50; Zn, 23.34.
Found: C, 40.63; H, 5.57; N, 7.39; Zn, 22.94. Yield of 14: 1.4 g
(44%). Anal. Calcd for C25H37N3O8Zn2 (14): C, 47.04; H, 5.84;
N, 6.58; Zn, 20.48. Found: C, 47.01; H, 5.75; N, 6.54; Zn, 20.06.
Yield of 15: 0.9 g (26%). Anal. Calcd for C28H49N3O8Zn2 (15):
C, 48.99; H, 7.19; N, 6.12; Zn, 19.05. Found: C, 48.94; H, 7.24;
N, 6.13; Zn, 20.04. Yield of 16: 0.9 g (16%). Anal. Calcd for
C34H44N6F12O12Zn3 (16): C, 35.42; H, 3.85; N, 7.29; F, 19.29; Zn,
17.01. Found: C, 35.23; H, 3.69; N, 6.99; F, 19.25; Zn, 17.43.
Preparation of 1-4. A solution of tmen (10 mmol) in methanol
was added slowly dropwise to a stirred solution of the appropriate
zinc carboxylate (10 mmol) in methanol. The reaction mixture was
stirred for 3 h, and the solvent evaporated by standing in air to
afford colorless crystals of 1, 2, 3, or 4, which were recrystallized
from diethyl ether. Yield of 1: 2.7 g, (81%). Anal. Calcd for
C10H22N2O4Zn (1): C, 40.08; H, 7.40; N, 9.35; Zn, 21.82. Found:
C, 40.08; H, 7.38; N, 9.33; Zn, 20.71. Yield of 2: 1.5 g, (43%).
Anal. Calcd for C14H28N2O5Zn (2): C, 46.61; H, 7.54; N, 7.77;
Zn, 18.12. Found: C, 46.83; H, 7.38; N, 7.79; Zn, 19.71. Yield of
(3): 2.8 g (35%). Anal. Calcd for C32H70N4O9Zn2 (3): C, 48.92;
H, 8.98; N, 7.13; Zn, 16.64. Found: C, 48.73; H, 8.93; N, 7.05;
Zn, 16.25. Yield of 4: 6.4 g (77%). Anal. Calcd for C20H34N4F12O9-
Zn2 (4): C, 28.83; H, 4.11; N, 6.72; F, 27.36; Zn, 15.69. Found:
C, 28.80; H, 4.01; N, 6.60; F, 26.88; Zn, 15.14.
Preparation of 17. A solution of BHA (10 mmol) in MeOH
was added dropwise to a solution of 8 (10 mmol) in MeOH and
stirred for 1 h. The solution was filtered and the filtrate concentrated
under vacuum to produce an oil, which was stirred in ether, filtered,
and the ether-insoluble portion recrystallized from CH2Cl2 to
produce colorless crystals of 17 suitable for X-ray crystallographic
analysis. Yield: 2.7 g (60%). Anal. Calcd for C15H14N5F3O4Zn:
C, 39.96; H, 3.13; N, 15.54; F, 12.65; Zn, 14.51. Found: C, 39.56;
H, 3.16; N, 15.02; F, 11.82; Zn, 13.90.
Preparation of 18 and 19. A solution of GluH2A2 (20 mmol)
in MeOH was added dropwise to a solution of 3 or 4 (10 mmol) in
MeOH and stirred for 1 h, filtered, and concentrated under vacuum.
The resulting residue was stirred in ether, filtered, and the filtrate
left to stand in air to produce colorless crystals of 18 or 19,
Preparation of 5-8. A solution of imidazole (20 mmol) in
methanol was added slowly dropwise to a stirred solution of the
appropriate zinc carboxylate (10 mmol) in methanol. The reaction
mixture was stirred for 3 h, filtered, and the solvent evaporated by
standing in air to afford colorless crystals of 5, 6, 7, or 8, which
were recrystallized from diethyl ether. Yield of 5: 2.1 g (66%).
Anal. Calcd for C10H14N4O4Zn (5): C, 37.58; H, 4.42; N, 17.53;
Zn, 20.46. Found: C, 37.25; H, 4.29; N, 17.30; Zn, 20.29. Yield
of 6: 0.8 g (22%). Anal. Calcd for C14H20N4O5Zn (6): C, 43.15;
H, 5.17; N, 14.38; Zn, 16.78. Found: C, 42.92; H, 4.85; N, 14.20;
Zn, 17.63. Yield of 7: 2.3 g (58%). Anal. Calcd for C16H28N4O5-
Zn (7): C, 46.56; H, 6.59; N, 13.57; Zn, 15.84. Found: C, 46.37;
H, 6.45; N, 13.45; Zn, 14.21. Yield of 8: 3.2 g (74%). Anal. Calcd
for C10H8N4F6O4Zn (8): C, 28.09; H, 1.89; N, 13.10; F, 26.11;
Zn, 14.98. Found: C, 28.70; H, 1.77; N, 14.45; F, 25.47; Zn, 15.35.
respectively. Yield of 18: 2.1 g (28%). Anal. Calcd for C59H126
-
N10O16Zn4 (18): C, 47.46; H, 8.50; N, 9.38; Zn, 17.51. Found: C,
46.75; H, 8.06; N, 8.94; Zn, 16.82. Yield of 19: 2.9 g (47%). Anal.
Calcd for C41H72N10F18O16Zn4 (19): C, 31.48; H, 4.64; N, 8.95; F,
21.86; Zn, 16.72. Found: C, 30.40; H, 4.52; N, 8.35; F, 21.73; Zn,
15.79.
Crystal Structure Determinations. Crystallographic data for
2, 4, 6-12, 16, 17, and 19 were collected using a Bruker D8
goniometer equipped with a Bruker SMART APEX CCD area
detector and a Mo KR X-ray tube. A full sphere of reciprocal space
was scanned by æ-ω scans. Semiempirical absorption correction,
based on redundant reflections, was performed by the program
SADABS.35 The structures were solved by direct methods using
SHELXTL-PC36 and refined by full matrix least-squares on F2 for
all data using SHELXL-97.37 Anisotropic displacement parameters
were refined for all non-hydrogen atoms.
Preparation of the Hydroxamic Acids. Hydroxamic acids were
prepared as described previously.33,34
Preparation of 9-12. A solution of AHA (10 mmol) in MeOH
was added dropwise to a solution of 1, 2, 3, or 4 (10 mmol) in
MeOH and stirred for 1 h. The solution was concentrated under
vacuum to produce an oil, which was stirred in ether, filtered, and
the ether washings were left to stand in air to produce colorless
crystals of 9, 10, 11, and 12, respectively. Yield of 9: 1.1 g (22%).
Anal. Calcd for C14H29N3O8Zn2 (9): C, 33.76; H, 5.87; N, 8.44;
Zn, 26.24. Found: C, 32.64; H, 5.87; N, 8.02; Zn, 26.72. Yield of
10: 1.2 g (42%). Anal. Calcd for C20H35N3O8Zn2 (10): C, 41.69;
H, 6.12; N, 7.29; Zn, 22.69. Found: C, 41.66; H, 6.31; N, 7.29;
Zn, 21.80. Yield of 11: 1.6 g (51%). Anal. Calcd for C23H47N3O8-
Zn2 (11): C, 44.24; H, 7.59; N, 6.73; Zn, 20.94. Found: C, 43.84;
H, 7.45; N, 6.83; Zn, 19.84. Yield of 12: 1.8 g (48%). Anal. Calcd
for C20H26N5F9O6Zn2 (12): C, 30.95; H, 4.67; N, 9.02; F, 22.03;
Zn, 16.84. Found: C, 30.10; H, 4.41; N, 8.54; F, 22.08; Zn, 16.27.
The treatment of the hydrogen atoms varies from compound to
compound, as crystal quality sometimes limited the options. Protons
of water molecules of crystallization were either located in the
difference Fourier map (2, 6, 9) or could not at all be detected (7).
In 2, the water proton (there is only one hydrogen site as the water
molecule occupies a 2-fold axis) was refined riding on the oxygen
atom, its isotropic displacement parameter fixed to 1.5 times the
equivalent displacement parameter of the oxygen atom. In 6 and
9, the water protons were refined freely including isotropic
displacement parameters.
The following noncrystal-water hydrogen atoms were refined
freely including isotropic displacement parameters: All of them
in 4, 6, 8, and 11, the ordered ones in 2 and 9, and those attached
to nitrogen in 10, 12, 16, 17, and 19. All remaining hydrogen atoms
were added at calculated positions and refined using a riding model.
Preparation of 13-16. A solution of BHA (10 mmol) in MeOH
was added dropwise to a solution of 1, 2, 3, or 4 (10 mmol) in
MeOH and stirred for 1 h. Almost immediately, [Zn(BA)2]‚H2O
formed as a white precipitatesan amorphous powder which is
unsuitable for X-ray crystallographic analysis. The solution was
filtered and the filtrate concentrated under vacuum to produce an
oil, which was stirred in ether, filtered, and the ether washings left
(35) Sheldrick, G. M. SADABS, Empirical Absorption Corrections Program;
University of Go¨ttingen: Go¨ttingen, Germany, 1996.
(36) Siemens SHELXTL-PC Version 5.0, Reference Manual; Siemens
Industrial Automation, Inc., Analytical Instrumentation: Madison, WI,
1994.
(37) Sheldrick, G. M. SHELXL97, Program for Crystal Structure Refine-
ment; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(33) Brown, D. A.; Roche, A. L. Inorg. Chem. 1983, 22, 2199.
(34) Brown, D. A.; N´ı Choilea´in, N.; Geraty, R. Inorg. Chem. 1986, 25,
3792.
4506 Inorganic Chemistry, Vol. 45, No. 11, 2006

Di-, Tri-, and Tetranuclear Zinc Hydroxamate Complexes
Figure 15. Summary of the reactions of the model complexes with hydroxamic acids.
Their isotropic displacement parameters were fixed to 1.2 times
(1.5 times for methyl groups) the equivalent isotropic displacement
parameters of the atom the H-atom is attached to.
complexes 1, 2, and 3 all react in identical ways with AHA
and BHA giving complexes of general formula [Zn2(O2CR)3-
(tmen)(R′A)], the reactions of 4 with AHA and BHA both
produce different products. The reaction with AHA results
in the formation of 15, which is structurally very similar to
the [Zn2(O2CR)3(tmen)(R′A)] complexes, with the exception
of the second tmen ligand. The M-M separations for the
complexes [Zn2(O2CR)3(tmen)(R′A)] (OAc, crot, piv) are all
∼3.2 Å, whereas the distance in the OAcF complexes are
all ∼3.6 Å.23,24 This larger M-M separation in the trifluo-
roacetate complexes is caused by the larger size of the OAcF
ion. This, combined with the strongly electron withdrawing
properties of the OAcF ion, allows a second tmen ligand to
coordinate to Zn2. In the BHA case, the added electron
withdrawing power of the benzene ring on the hydroxamate
allows two [Zn2(OAcF)3(tmen)(BA)] units to combine to form
16, instead of simply adding a second tmen as in the case of
15. Finally, care must be taken when using alternative metals
to study the zinc enzymes, e.g., cobalt substitution.
Conclusions
We have shown that the bridging mode of coordinated
hydroxamate as observed previously15-24 is conserved in the
multinuclear zinc-hydroxamate complexes described here.
However, unlike the bis-hydroxamate bridged complexes
[M2(µ-O2CR)(R′A)2(tmen)2][O2CR] (M ) Ni, Co, Mn; R )
CH3, C(CH3)3), the zinc-hydroxamate species contain only
a single bridging hydroxamate. It is this singly bridging motif
that is in fact observed in the X-ray crystal structures of
hydrolases inhibited by hydroxamic acids.16-18 The presence
of hydrogen bonding between the dangling oxygen of the
monodentate carboxylate and the NH of the hydroxamate in
[Zn2(O2CR)3(tmen)(R′A)] may be important in the formation
of the hydroxamate dinuclear complex, since the reactions
of 1, 2, 3, and 4 with the N-substituted hydroxamic acids
failed to produce dinuclear hydroxamate complexes (Figure
15). The above H-bonding in [Zn2(O2CR)3(tmen)(R′A)]
models closely that observed between the hydroxamate NH
and the free oxygen of Glu151 in Aeromonas proteolytica
aminopeptidase (Zn2AAP) inhibited by p-iodo-D-phenylala-
nine hydroxamic acid.18,24 GluH2A2 fails to react with the
mononuclear 1 and 2, but on reaction with the dinuclear 3
and 4, the tetranuclear complexes 18 and 19 are formed
(Figure 15), in contrast to the Ni and Co series where the
reaction of [M2(O2CR)4(µ-H2O)(tmen)2] (M ) Ni, Co) with
GluH2A2 gives the ion [M2(O2CR){µ-O(N)(OC)2(CH2)3}-
(tmen)2]+, with elimination of hydroxylamine. It is probably
the coordinative flexibility of the Zn2+ ion that allows the
formation of the flexible neutral species [Zn4(O2CR)6(tmen)4-
(GluA2)] in preference to the highly strained cyclic ionic
product [M2(O2CR){µ-O(N)(OC)2(CH2)3}(tmen)2]+. While
Acknowledgment. We gratefully acknowledge support
from the following bodies: EU COST D21 Project D21/
0001/00; Centre for Synthesis and Chemical Biology, Con-
way Institute of Biomolecular and Biomedical Research,
University College Dublin. We also thank Ms. Anne Con-
nolly of the microanalytical laboratory, Chemical Services
Unit, University College Dublin, who performed the elemen-
tal analyses.
Supporting Information Available: Tables of NMR and IR
data for all complexes; CIF files for structures 2, 4, 6, 7, 8, 9, 10,
11, 12, 16, 17, and 19; and selected bond lengths and angles and
ORTEP figures. This material is available free of charge via the
Internet at http://pubs.acs.org.
IC050849M
Inorganic Chemistry, Vol. 45, No. 11, 2006 4507