Synthesis and characterization of mononuclear zinc aryloxide complexes supported by nitrogen/sulfur ligands possessing an internal hydrogen bond donor

Article abstract of DOI:10.1021/ic020031q

Treatment of a dinuclear zinc hydroxide complex ([(bmnpaZn)₂(μ-OH)₂](ClO₄)₂ (1) or [(benpaZn)₂(μ-OH)₂](ClO₄)₂ (2)) with excess equivalents of an aryl alcohol derivative (p-HOC₆H₄X; X = NO₂, CHO, CN, COCH₃, Br, H, OCH₃) yielded the nitrogen/sulfur-ligated zinc aryloxide complexes [(bmnpa)Zn(p-OC₆H₄NO₂)](ClO₄) (3), [(benpa)Zn(p-OC₆H₄NO₂)](ClO₄) (4), [(benpa)Zn(p-OC₆H₄CHO)](ClO₄) (5), [(benpa)Zn(p-OC₆H₄CN)](ClO₄) (6), [(benpa)Zn(p-OC₆H₄COCH₃)] (ClO₄)·O.5H₂O (7), [(benpa)Zn(p-OC₆H₄Br)](ClO₄) (8), [(benpa)Zn(p-OC₆H₅)](ClO₄) (9), and [(benpa)Zn(p-OC₆H₅OCH₃)](ClO₄) (10). The solid state structures of 2, 3, 5, and 6 have been determined by X-ray crystallography. While 3 and 6 exhibit a mononuclear zinc ion possessing a distorted five-coordinate trigonal bipyramidal geometry, in 5 each zinc center exhibits a distorted six-coordinate octahedral geometry resulting from coordination of the aldehyde carbonyl oxygen of another zinc-bound aryloxide ligand, yielding a chain-type structure. Zinc coordination of the aldehyde carbonyl of 5 is indicated by a large shift (>40 cm^-1) to lower energy of the carbonyl stretching vibration (v_c=o) in solid state FTIR spectra of the complex. In the solid state structures of 3, 5, and 6, a hydrogen-bonding interaction is found between N(3)-H of the supporting bmnpa/benpa ligand and the zinc-bound oxygen atom of the aryloxide ligand (N(3)···0(1) ～ 2.78 A). Solution ¹H and ¹³C NMR spectra of 3-10 in CD₃CN and FTIR spectra in CH₃CN are consistent with all of the aryloxide complexes having a similar solution structure, with retention of the hydrogen-bonding interaction involving N(3)-H and the oxygen atom of the zinc-coordinated aryloxide ligand. For this family of zinc aryloxide complexes, a correlation was discovered between the chemical shift position of the N(3)-H proton resonance and the pK_a of the parent aryl alcohol. This correlation indicates that the strength of the hydrogen-bonding interaction involving the zinc-bound aryloxide oxygen is increasing as the aryloxide moiety increases in basicity.

Full text of DOI:10.1021/ic020031q

Inorg. Chem. 2002, 41, 3533−3541
Synthesis and Characterization of Mononuclear Zinc Aryloxide
Complexes Supported by Nitrogen/Sulfur Ligands Possessing an
Internal Hydrogen Bond Donor
,†
Dewain K. Garner,† Russell A. Allred,† Kyle J. Tubbs,† Atta M. Arif,‡ and Lisa M. Berreau*
Department of Chemistry and Biochemistry, Utah State UniVersity, Logan, Utah 84322-0300, and
Department of Chemistry, UniVersity of Utah, Salt Lake City, Utah 84112
Received January 10, 2002
Treatment of a dinuclear zinc hydroxide complex ([(bmnpaZn)2(µ-OH)2](ClO ) (1) or [(benpaZn)2(µ-OH)2](ClO )
4 2
4 2
(2)) with excess equivalents of an aryl alcohol derivative (p-HOC H X; X ) NO , CHO, CN, COCH , Br, H, OCH )
6
4
2
3
3
yielded the nitrogen/sulfur-ligated zinc aryloxide complexes [(bmnpa)Zn(p-OC H NO )](ClO ) (3), [(benpa)Zn(p-
6
4
2
4
OC H NO )](ClO ) (4), [(benpa)Zn(p-OC H CHO)](ClO ) (5), [(benpa)Zn(p-OC H CN)](ClO ) (6), [(benpa)Zn(p-OC H -
6
4
2
4
6
4
4
6
4
4
6 4
COCH )](ClO )‚0.5H O (7), [(benpa)Zn(p-OC H Br)](ClO ) (8), [(benpa)Zn(p-OC H )](ClO ) (9), and [(benpa)Zn(p-
3
4
2
6
4
4
6
5
4
OC H OCH )](ClO ) (10). The solid state structures of 2, 3, 5, and 6 have been determined by X-ray crystallography.
6
5
3
4
While 3 and 6 exhibit a mononuclear zinc ion possessing a distorted five-coordinate trigonal bipyramidal geometry,
in 5 each zinc center exhibits a distorted six-coordinate octahedral geometry resulting from coordination of the
aldehyde carbonyl oxygen of another zinc-bound aryloxide ligand, yielding a chain-type structure. Zinc coordination
of the aldehyde carbonyl of 5 is indicated by a large shift (>40 cm-1) to lower energy of the carbonyl stretching
vibration (νCdO) in solid state FTIR spectra of the complex. In the solid state structures of 3, 5, and 6, a hydrogen-
bonding interaction is found between N(3)−H of the supporting bmnpa/benpa ligand and the zinc-bound oxygen
atom of the aryloxide ligand (N(3)‚‚‚O(1) ∼ 2.78 Å). Solution 1H and 13C NMR spectra of 3−10 in CD CN and
3
FTIR spectra in CH CN are consistent with all of the aryloxide complexes having a similar solution structure, with
3
retention of the hydrogen-bonding interaction involving N(3)−H and the oxygen atom of the zinc-coordinated aryloxide
ligand. For this family of zinc aryloxide complexes, a correlation was discovered between the chemical shift position
of the N(3)−H proton resonance and the pK of the parent aryl alcohol. This correlation indicates that the strength
a
of the hydrogen-bonding interaction involving the zinc-bound aryloxide oxygen is increasing as the aryloxide moiety
increases in basicity.
Introduction
undergoes deprotonation to yield a zinc-bound alkoxide
species, which is suggested to be the active complex for
hydride transfer to NAD+.2 An active site residue that
interacts with the zinc-bound alkoxide is Ser48. As shown in
Scheme 1, this residue is proposed to donate a hydrogen bond
to the oxygen atom of the zinc-bound alkoxide.2 Structural
or spectroscopic parameters for this Ser48 hydrogen-bonding
interaction involving a zinc-alkoxide species in LADH have
not been reported.3 However, structurally characterized forms
of LADH inhibited by formamides4 or sulfoxides5 exhibit a
The zinc-containing enzyme liver alcohol dehydrogenase
(LADH) catalyzes the two-electron oxidation of an alcohol
to an aldehyde or ketone, coupled with reduction of NAD+
to NADH.1 In the resting state, the tetrahedral ligand
environment of the active site zinc ion in LADH is composed
of a histidine nitrogen donor, two cysteine thiolate sulfur
donors, and a water/hydroxo moiety. During catalytic
turnover, it is proposed the zinc-bound alcohol substrate
* Corresponding author. E-mail: berreau@cc.usu.edu. Phone: (435) 797-
1625. Fax: (435) 797-3390.
(2) Ramaswamy, S.; Park, D.-H.; Plapp, B. V. Biochemistry 1999, 38,
13951-13959.
(3) A calculated O(Ser48)‚‚‚O(alkoxide) distance (2.44 Å) was recently
reported. Agarwal, P. K.; Webb, S. P.; Hammes-Schiffer, S. J. Am.
Chem. Soc. 2000, 122, 4803-4812.
† Utah State University.
‡ University of Utah.
(1) Eklund, H.; Bra¨nde´n, C.-I. In Zinc Enzymes; Spiro, T. G., Ed.;
Wiley: New York, 1983; pp 124-152.
10.1021/ic020031q CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/07/2002
Inorganic Chemistry, Vol. 41, No. 13, 2002 3533

Garner et al.
elusive synthetic targets.11,12 This is likely due in part to the
dearth of known nitrogen/sulfur-ligated zinc hydroxide
species,13 molecules that may serve as synthetic precursors
to alkoxide/aryloxide derivatives.
Scheme 1. Hydrogen-Bonding Interactions in LADH Involving Ser48
In our laboratory, we have developed a family of nitrogen/
sulfur(thioether) ligands possessing a single internal hydrogen
bond donor. While these ligands possess neutral sulfur
donors, versus the anionic cysteine sulfur donors found in
LADH, they have proven suitable for isolating several
complexes relevant to this enzyme. Specifically, by using
thioether sulfur donors in our ligands, we can prevent the
formation of thiolate bridged polymetallic complexes,14 and
hence produce zinc complexes with available coordination
sites for binding of small molecules relevant to substrate or
inhibitors. For example, using the bmapa ligand (N,N-bis-
2-(methylthio)ethyl-N-(6-amino-2-pyridylmethyl)amine), we
recently prepared and structurally characterized mononuclear
zinc alcohol and formamide complexes relevant to substrate
and inhibitor-bound forms of LADH.15 Importantly, the N,N-
dimethylformamide complex exhibits a secondary hydrogen-
bonding interaction akin to that involving Ser48 in the
formamide-inhibited form of LADH.4
We have also demonstrated that another member of this
ligand family (N,N-bis-2-(methylthio)ethyl-N-(6-neopentyl-
amino-2-pyridylmethyl)amine, bmnpa) enables the isolation
of a mononuclear nitrogen/sulfur-ligated zinc complex pos-
sessing a single bound anion (perchlorate).13 This anion
accepts a hydrogen bond from the secondary amine donor
of the bmnpa ligand, thus providing an indication that the
bmnpa ligand system may prove suitable for isolation of
novel complexes possessing a single bound alkoxide or
aryloxide ligand. Herein, we outline our initial exploration
of the reactions of zinc hydroxide complexes of the bmnpa
and benpa (N,N-bis-2-(ethylthio)ethyl-N-(6-neopentylamino-
2-pyridylmethyl)amine) ligands with several aryl alcohols.
Through this work, we demonstrate that these ligand sets
enable the isolation and characterization of mononuclear
nitrogen/sulfur-ligated zinc aryloxide complexes possessing
a hydrogen-bonding interaction akin to that proposed to occur
between Ser48 and a zinc-bound alkoxide in the active form
of LADH. Furthermore, we outline how this hydrogen-
bonding interaction is perturbed by changes in the basicity
of the zinc-bound aryloxide ligand.
hydrogen-bonding interaction between Ser48 (H-bond donor)
and the zinc-bound oxygen atom of the inhibitor (H-bond
acceptor) that is likely similar to that involving the zinc-
bound alkoxide. The hydrogen-bonding interactions found
in these inhibited forms of LADH are characterized by short
heteroatom distances (O(Ser48)‚‚‚O(inhibitor), ∼2.6 Å).6
Despite the synthesis of zinc complexes of several new
mixed nitrogen/sulfur ligand systems in recent years,7-10
synthetic zinc alkoxide or aryloxide complexes possessing
a mixed nitrogen/sulfur coordination environment remain
(4) Ramaswamy, S.; Scholze, M.; Plapp, B. V. Biochemistry 1997, 36,
3522-3527.
(5) Al-Karadaghi, S.; Cedergren-Zeppezauer, E.; Ho¨vmoller, S.; Petratos,
K.; Terry, H.; Wilson, K. S. Acta Crystallogr. 1994, D50, 793-807.
(6) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford University
Press: New York, 1997.
(7) For example, see: (a) Seebacher, J.; Shu, M. H.; Vahrenkamp, H.
Chem. Commun. 2001, 1026-1027 and references therein. (b) Burth,
R.; Stange, A.; Scha¨fer, M.; Vahrenkamp, H. Eur. J. Inorg. Chem.
1998, 1759-1764. (c) Brand, U.; Vahrenkamp, H. Inorg. Chem. 1995,
34, 3285-3293. (d) Brand, U.; Vahrenkamp, H. Chem. Ber. 1996,
129, 435-440.
(8) (a) Parkin, G. Chem. Commun. 2000, 1971-1985. (b) Ghosh, P.;
Parkin, G. Chem. Commun. 1998, 413-414. (c) Kimblin, C.; Hascall,
T.; Parkin, G. Inorg. Chem. 1997, 36, 5680-5681. (d) Kimblin, C.;
Bridgewater, B. M.; Churchill, D. G.; Hascall, T.; Parkin, G. Inorg.
Chem. 2000, 39, 4240-4243.
(9) (a) Chiou, S.-J.; Innocent, J.; Riordan, C. G.; Lam, K.-C.; Liable-
Sands, L. M.; Rheingold, A. L. Inorg. Chem. 2000, 39, 4347-4353.
(b) Chiou, S.-J.; Ge, P.; Riordan, C. G.; Liable-Sands, L. M.;
Rheingold, A. L. Chem. Commun. 1999, 159-160.
(10) (a) Chang, S.; Karambelkar, V. V.; diTargiani, R. C.; Goldberg, D.
P. Inorg. Chem. 2001, 40, 194-195. (b) Shoner, S. C.; Humphreys,
K. J.; Barnhart, D.; Kovacs, J. A. Inorg. Chem. 1995, 34, 5933-
5934.
(11) Mononuclear zinc aryloxide/alkoxide complexes: (a) Tesmer, M.; Shu,
M.; Vahrenkamp, H. Inorg. Chem. 2001, 40, 4022-4029. (b) Walz,
R.; Weis, K.; Ruf, M.; Vahrenkamp, H. Chem. Ber. 1997, 130, 975-
980. (c) Kimura, E.; Kodama, Y.; Koike, T.; Shiro, M. J. Am. Chem.
Soc. 1995, 117, 8304-8311. (d) Kimura, E.; Nakamura, I.; Koike,
T.; Shionoya, M.; Kodama, Y.; Ikeda, T.; Shiro, M. J. Am. Chem.
Soc. 1994, 116, 4764-4771. (e) Bergquist, C.; Storrie, H.; Koutcher,
L.; Bridgewater, B. M.; Friesner, R. A.; Parkin, G. J. Am. Chem. Soc.
2000, 122, 12651-12658. (f) Hammes, B. S.; Carrano, C. J. Dalton
Trans. 2000, 3304-3309.
(12) Mononuclear zinc alkoxide complexes ligated by tris(pyrazolyl)-
hydroborato supporting ligands are known and have been studied as
model systems for the active form of LADH: Bergquist, C.; Parkin,
G. Inorg. Chem. 1999, 38, 422-423.
(13) Berreau, L. M.; Allred, R. A.; Makowska-Grzyska, M. M.; Arif, A.
M. Chem. Commun. 2000, 1423-1424.
(14) Burth, R.; Stange, A.; Scha¨fer, M.; Vahrenkamp, H. Eur. J. Inorg.
Chem. 1998, 1759-1764 and references cited therein.
(15) Berreau. L. M.; Makowska-Grzyska, M. M.; Arif, A. M. Inorg. Chem.
2001, 40, 2212-2213.
3534 Inorganic Chemistry, Vol. 41, No. 13, 2002

N/S-Ligated Zinc Aryloxide Complexes
Et2O (20 mL). The precipitate obtained from this solution was taken
up in CH3CN (∼10 mL), stirred vigorously for 20 min, and then
filtered through a Celite/glass wool plug. Diethyl ether diffusion
into this CH3CN solution at ambient temperature yielded colorless
crystalline blocks suitable for X-ray diffraction (0.13 g, 84%). The
Experimental Section
All reagents and solvents were obtained from commercial sources
and were used as received unless otherwise noted. Solvents were
dried according to published procedures16 and were distilled under
N2 prior to use. Synthetic reactions leading to the formation of the
zinc aryloxide complexes were performed in a MBraun Unilab
glovebox under an atmosphere of purified N2. The ligand bmnpa
and the dinuclear zinc hydroxide complex [(bmnpaZn)2(µ-OH)2]-
(ClO4)2 (1) were prepared as previously reported.13
1
product was pure by H NMR. FTIR (KBr, cm-1): 3534 (νO-H),
3234 (νN-H), 1105 (νClO ), 624 (νClO ). Anal.Calcd for C38H72N6O10S4-
4
4
Cl2Zn2: C, 41.52; H, 6.61; N, 7.65. Found: C, 40.02; H, 6.43; N,
7.37. Repeated attempts (three) at elemental analysis of this complex
each time yielded a carbon content that is notably below the
calculated value. We speculate that this may be due to the presence
of trace amounts of KClO4 that we have been unable to separate
from the crystalline product. However, as shown below, aryloxide
derivatives prepared from this zinc hydroxide complex are analyti-
cally pure.
Physical Methods. FTIR spectra were recorded on a Shimadzu
FTIR-8400 spectrometer as KBr pellets or as CH3CN or CH2Cl2
solutions (∼100 mM) between NaCl plates. 1H and 13C{1H} NMR
spectra were recorded in dry CD3CN at 20(1) °C on a JEOL GSX-
270 or Bruker ARX400 spectrometer. Chemical shifts (in ppm)
are referenced to the residual solvent peak(s) (1H, 1.96 (quintet);
13C{1H}, 1.39 (heptet) ppm). 1H and 13C NMR data for 2-10 may
be found in Tables S3 and S4 of the Supporting Information.
Elemental analyses were performed by Atlantic Microlabs of
Norcross, GA.
General Method for the Preparation of [(bmnpa)Zn(p-
OC6H4X)]ClO4 and [(benpa)Zn(p-OC6H4X)]ClO4 Complexes
(bmnpa, X ) NO2 (3); benpa, X ) NO2 (4), CHO (5), CN (6),
COCH3 (7), Br (8), H (9), OCH3 (10)). Part 1. In Situ
Preparation of Zinc Hydroxide Complexes. Under atmospheric
conditions, 0.11 g (0.29 mmol) of Zn(ClO4)2‚6H2O was dissolved
in methanol (2 mL). To this solution was added a pale yellow
methanol solution (1 mL) of bmnpa (0.11 g, 0.31 mmol) or benpa
(0.11 g, 0.28 mmol). The resulting mixture was stirred for 30 min
at room temperature. At this point, a clear methanol solution of
KOH (0.014 g, 0.30 mmol) was added and the solution was stirred
for an additional 30 min. Excess Et2O (∼40 mL) was added, and
the resulting cloudy solution was cooled to ∼ -30 °C for 12 h.
The solid that had deposited during this time was dried under
vacuum. This solid was then dissolved in acetonitrile (5 mL), and
an excess of Et2O was added, leading to the rapid precipitation of
a white solid, which was collected, dried under vacuum, and
identified as either [(bmnpaZn)2(µ-OH)2](ClO4)2 (1) or [(benpaZn)2-
CAUTION! Perchlorate salts of metal complexes with organic
ligands are potentially explosiVe. Only small amounts of material
should be prepared, and these should be handled with great care.17
N,N-Bis-2-(ethylthio)ethyl-N-(6-neopentylamino-2-pyridyl-
methyl)amine (benpa). To a 500 mL round bottom flask was added
0.84 g (0.022 mol) LiAlH4 followed by a solution of 35 mL of dry
pyridine in 90 mL of dry THF. To this solution was added 2.6 g
(0.0067 mol) of beppa (N,N-bis-2-(ethylthio)ethyl-N-(6-pivaloyl-
amido-2-pyridylmethyl)amine)18 dissolved in 85 mL of THF. The
resulting solution was heated at reflux under a N2 atmosphere for
14 h. After cooling the reaction mixture to ambient temperature,
an equal volume of water was added, with the initial addition being
done dropwise to minimize vigorous bubbling and emulsion
formation. Extraction of the mixed organic/aqueous reaction mixture
with EtOAc (3 × 100 mL), followed by drying of the combined
organic fractions with Na2SO4, filtration, and removal of the solvent
under reduced pressure, yielded a thick yellow oil. The analytically
pure ligand (benpa) was isolated following column chromatography
(ethyl acetate, 200-400 mesh silica gel, Rf ∼ 0.82) as a yellow oil
1
(µ-OH)2](ClO4)2 (2) by H NMR spectroscopy.
Part 2. Reaction of Zinc Hydroxide Complexes with Aryl
Alcohols. Note: Dry solVents were employed throughout this
procedure. Under a dry, inert atmosphere, an acetonitrile (5 mL)
solution of an excess (>4 equiv) molar amount of the desired phenol
was added to 1 molar equiv of solid zinc hydroxide complex (1 or
2). The resulting slurry was stirred for 30 min, at which time the
solvent was removed under reduced pressure. The dried solid was
then dissolved in CH2Cl2 (5 mL) and filtered, and the filter cake
was rinsed with several additional washes of methylene chloride
(total volume ∼10 mL). The volume of the filtrate solution was
then reduced under vacuum to ∼5 mL, excess Et2O was added
(∼15 mL), and the resulting cloudy solution was cooled to
∼ -20(1) °C for 12 h. The solid that had deposited was then dried
under reduced pressure. Recrystallization of the product from diethyl
ether diffusion into an acetonitrile solution containing an excess
of the appropriate parent aryl alcohol (∼0.015 g) yielded crystals
suitable for X-ray diffraction analysis.
1
(73%). H NMR (CD3CN, 270 MHz): δ 7.32 (t, J ) 7.6, 1H),
6.60 (d, J ) 7.2, 1H), 6.33 (d, J ) 8.3, 1H), 5.00 (t, J ) 5.6 Hz,
1H, N-H), 3.56 (s, 2H), 3.13 (d, J ) 6.3 Hz, 2H), 2.80-2.57 (m,
8H), 2.49 (q, J ) 7.2 Hz, 4H), 1.18 (t, J ) 7.2 Hz, 6H), 0.93 (s,
9H). 13C{1H} NMR (CD3CN, 67.9 MHz): δ 160.2, 158.6, 138.2,
111.8, 106.3, 60.5, 55.1, 53.5, 32.9, 30.0, 27.9, 26.5, 15.4 (13 signals
expected and observed). FTIR (neat, cm-1): ∼3400 (br, νN-H).
Anal. Calcd for C19H35N3S2: C, 61.75; H, 9.55; N, 11.38. Found:
C, 61.04; H, 9.62; N, 10.87.
[(benpaZn)2(µ-OH)2](ClO4)2 (2). A methanol solution (1 mL)
of benpa (0.10 g, 0.29 mmol) was added to methanol solution (2
mL) of Zn(ClO4)2‚6H2O (0.10 g, 0.27 mmol). The resulting solution
was stirred for ∼30 min at ambient temperature, at which time a
methanol solution (2 mL) of KOH (0.013 g, 0.28 mmol) was added.
Following 30 min of rapid stirring, an excess of diethyl ether (15
mL) was added and the resulting cloudy mixture was cooled to
∼ -28 °C for 30 min. A white solid that had deposited was then
collected and dried briefly under vacuum. The solid precipitate
obtained was then slurried in CH3CN and was again added to excess
[(bmnpa)Zn(p-OC6H4NO2)]ClO4 (3). Yield: 137 mg, 73%.
FTIR (KBr, cm-1): 3220 (br, νN-H), 1299 (νC-O), 1086 (νClO ),
4
623 (νClO ). Anal. Calcd for C23H35O7N4S2ClZn: C, 42.98; H, 5.49;
4
N, 8.72. Found: C, 43.35; H, 5.57; N, 8.81.
[(benpa)Zn(p-OC6H4NO2)]ClO4 (4). Yield: 110 mg, 62%.
FTIR (KBr, cm-1): 3220 (br, νN-H), 1301 (νC-O), 1087 (νClO ),
4
622 (νClO ). Anal. Calcd for C25H39O7N4S2ClZn: C, 44.77; H, 5.87;
4
N, 8.36. Found: C, 44.46; H, 5.50; N, 8.39.
(16) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon Press: New York, 1988.
(17) Wolsey, W. C. J. Chem. Educ. 1973, 50, A335-A337.
(18) Berreau, L. M.; Makowska-Grzyska, M. M.; Arif, A. M. Inorg. Chem.
2000, 39, 4390-4391.
[(benpa)Zn(p-OC6H4CHO)]ClO4 (5). Yield: 120 mg, 66%.
FTIR (KBr, cm-1): 3254 (br, νN-H), 1301 (νC-O), 1088 (νClO ),
4
623 (νClO ). FTIR (∼100 mM CH2Cl2, cm-1): 1685 (νCdO). FTIR
4
(∼100 mM CH3CN, cm-1): 1680 (νCdO). Anal. Calcd for
Inorganic Chemistry, Vol. 41, No. 13, 2002 3535

Garner et al.
Scheme 2
C26H40O6N3S2ClZn: C, 47.77; H, 6.17; N, 6.43. Found: C, 47.45;
H, 6.18; N, 6.53.
[(benpa)Zn(p-OC6H4CN)]ClO4 (6). Yield: 112 mg, 61%. FTIR
(KBr, cm-1): 3213 (νN-H), 2219 (νCtN), 1305 (νC-O), 1087 (νClO ),
4
622 (νClO ). Anal. Calcd for C26H39O5N4S2ClZn: C, 47.99; H, 6.05;
4
N, 8.62. Found: C, 47.89; H, 6.00; N, 8.54.
[(benpa)Zn(p-OC6H4COCH3)]ClO4‚0.5H2O (7). Yield: 112
mg, 59%. FTIR (KBr, cm-1): 3246 (νN-H), 1648 (νCdO), 1301
(νC-O), 1088 (νClO ), 623 (νClO ). FTIR (∼100 mM CH2Cl2, cm-1):
4
4
1662 (νCdO). FTIR (∼100 mM CH3CN, cm-1): 1662 (νCdO). Anal.
Calcd for C27H42O6N3S2ClZn‚0.5H2O: C, 47.92; H, 6.41; N, 6.21.
Found: C, 47.77; H, 6.35; N, 6.30.
[(benpa)Zn(p-OC6H4Br)]ClO4 (8). Yield: 129 mg, 66%. FTIR
(KBr, cm-1): 3209 (νN-H), 1279 (νC-O), 1091 (νClO ), 623 (νClO ).
4
4
Anal. Calcd for C25H39O5N3S2ClBrZn: C, 42.67; H, 5.59; N, 5.98.
Found: C, 42.25; H, 5.34; N, 5.58.
[(benpa)Zn(OC6H5)]ClO4 (9). Yield: 107 mg, 61%. FTIR (KBr,
cm-1): 3220 (νN-H), 1267 (νC-O), 1087 (νClO ), 623 (νClO ). Anal.
4
4
Calcd for C25H40O5N3S2ClZn: C, 47.99; H, 6.45; N, 6.72. Found:
C, 47.66; H, 6.32; N, 6.50.
[(benpa)Zn(p-OC6H5OCH3)]ClO4 (10). Yield: 114 mg, 64%.
FTIR (KBr, cm-1): 3220 (νN-H), 1261 (νC-O), 1232 (νC-O), 1086
(νClO ), 623 (νClO ). Anal. Calcd for C26H42O6N3S2ClZn: C, 47.62;
4
4
H, 6.46; N, 6.41. Found: C, 48.04; H, 6.76; N, 6.11.
X-ray Crystallography. A crystal of each compound 2, 3, 5,
and 6 was mounted on a glass fiber with traces of viscous oil and
then transferred to a Nonius KappaCCD diffractometer with Mo
KR radiation (λ ) 0.71073 Å) for data collection at 200(1) K. For
each compound, an initial set of cell constants was obtained from
10 frames of data that were collected with an oscillation range of
1 deg/frame and an exposure time of 20 s/frame. Indexing and unit
cell refinement based on observed reflections from those 10 frames
indicated monoclinic P lattices for 2, 3, 5, and 6. Final cell constants
for each complex were determined from a set a strong reflections
from the actual data collection. For each data set, these reflections
were indexed, integrated, and corrected for Lorentz, polarization,
and absorption effects using DENZO-SMN, SCALEPAC, and
Multi-scan.19 The structures were solved by a combination of direct
methods and heavy atom using SIR 97. All of the non-hydrogen
atoms were refined with anisotropic displacement coefficients.
Unless otherwise stated, hydrogen atoms were assigned isotropic
displacement coefficients U(H) ) 1.2U(C) or 1.5U(Cmethyl), and
their coordinates were allowed to ride on their respective carbons
using SHELXL97.
Structure Solution and Refinement. Crystals of 2 were
determined to belong to the monoclinic crystal system. Systematic
absences in the data for the zinc hydroxide complex [(benpaZn)2-
(µ-OH)2](ClO4)2 (2) were consistent with the space group P21/n.
Hydrogen atoms were located and refined independently except
those on C(5), C(5′), C(6), and C(6′), which were assigned isotropic
displacement coefficients, and their coordinates were allowed to
ride on their respective carbons. The carbon atoms of one thioether
ethyl group of the benpa ligand exhibit disorder. These carbon atoms
(C(5)/C(6)) were each split into two fragments (second fragment
denoted by a prime) and were refined. This refinement led to a
0.48:0.52 ratio in occupancy over two positions for each carbon
atom. The p-nitroaryloxide complex 3 crystallizes in the space group
P21/a. Hydrogen atom H(3) was located and refined independently.
The p-hydroxybenzaldehyde derivative 4 crystallizes in the space
group P21/n. All hydrogen atoms were located and refined
independently. The p-cyanoaryloxide complex 6 crystallizes in the
space group P21/a. Hydrogen atoms were located and refined
independently except those on C(5) and C(6), which were assigned
isotropic displacement coefficients, and their coordinates were
allowed to ride on their respective carbons.
Results
Syntheses. Treatment of the dinuclear zinc hydroxide
complexes [(bmnpaZn)2(µ-OH)2](ClO4)2 (1) or [(benpaZn)2-
(µ-OH)2](ClO4)2 (2) with an excess (typically ∼4 equiv) of
an aryl alcohol derivative (p-HOC6H4X; X ) NO2, CHO,
CN, COCH3, H, Br, OCH3; Scheme 2) yielded a series of
nitrogen/sulfur-ligated zinc aryloxide complexes (3-10). The
rationale for using excess equivalents of the aryl alcohol was
the presence of trace amounts of [(benpaZn)2(µ-OH)2](ClO4)2
in isolated samples of some of the aryloxide complexes
prepared under strictly stoichiometric conditions. Recrystal-
lization of each complex from CH3CN:Et2O yielded an
analytically pure crystalline material. Notably, the p-hy-
droxyacetophenone derivative 7 was consistently isolated
with ∼0.5 equiv of water present, even after prolonged drying
1
under reduced pressure. Elemental analysis and H NMR
spectroscopy confirmed the presence of this water. In general,
the aryloxide complexes are stable in dry CD3CN solution
for several days.
X-ray Crystallography. The structure of the zinc hy-
droxide derivative [(benpaZn)2(µ-OH)2](ClO4)2 (2) was
determined by X-ray crystallography. Due to its nearly
identical structural properties to the previously reported
[(bmnpaZn)2(µ-OH)2](ClO4)2 (1), the metric features of this
(19) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307-326.
3536 Inorganic Chemistry, Vol. 41, No. 13, 2002

N/S-Ligated Zinc Aryloxide Complexes
Table 1. Details of X-ray Data Collection and Refinement for 3, 5, and 6
[(bmnpa)Zn(p-OC6H4NO2)]ClO4 (3)
[(benpa)Zn(p-OC6H4CHO)]ClO4 (5)
[(benpa)Zn(p-OC6H4CN)]ClO4 (6)
empirical formula
fw
C23H35ClN4O7S2Zn
644.49
C26H40ClN3O6S2Zn
655.55
C26H39ClN4O5S2Zn
652.55
space group
a, Å
b, Å
P21/a
15.8941(5)
9.3054(2)
19.8964
P21/n
P21/a
13.0722(3)
13.2501(3)
18.3831(4)
90
107.1365(9)
90
15.2217(2)
9.6944(2)
20.6876(4)
90
97.0568(7)
90
c, Å
R, deg
90
â, deg
99.3345(12)
90
2903.73(15)
4
γ, deg
V, Å3
3042.74(12)
4
3029.65(9)
4
Z
cryst color, habit
cryst size, mm3
D(calcd), g cm-3
µ(Mo KR), mm-1
temp, K
colorless thin plate
colorless prism
0.25 × 0.25 × 0.10
1.431
1.075
200(1)
colorless plate
0.23 × 0.18 × 0.13
1.431
1.078
200(1)
0.25 × 0.25 × 0.05
1.474
1.129
200(1)
diffractometer
radiation
Nonius KappaCCD
Nonius KappaCCD
Mo KR (0.71073 Å)
11638
6921
512
4.42
9.12
1.042
-0.467, 0.770
Nonius KappaCCD
Mo KR (0.71073 Å)
11950
6925
489
4.76
9.50
1.022
-0.562, 0.719
Mo KR (0.71073 Å)
12116
6623
352
4.67
9.84
1.027
-0.646, 0.968
reflns collcd
indep reflns
params
R(F), %a
R(wF2), %a
GOF on F2 b
min and max resid dens, e Å-3
2
2
2
2
a R(wF2) ) [∑(wFo2 - Fc )/∑(Fo )2]1/2, R ) ∑(||Fo| - |Fc||)/∑|Fo|; for 3, w ) 1/[σ2(Fo ) + (0.0429P)2 + 2.1924P]; for 5, w ) 1/[σ2(Fo ) + (0.0441P)2
+ 0.4838P]; and for 6, w ) 1/[σ2(Fo ) + (0.0486P)2 + 0.2698P], where P ) (Fo2 + 2Fc )/3. b Goodness of fit on F2 ) [∑(w(Fo2 - Fc )/(n - p)]1/2, where
n is the number of reflections and p is the number of parameters refined.
2
2
2
Table 2. Selected Bond Distances (Å) and Angles (deg)
3
5
6
Zn(1)-O(1)
Zn(1)-O(2)•2
Zn(1)-S(1)
Zn(1)-S(2)
Zn(1)-N(1)
Zn(1)-N(2)
C(18)-O(1)
C(20)-O(1)
C(26)-O(2)
1.950(2)
1.962(2)
2.2283(19)
2.5801(8)
2.5760(8)
2.212(2)
2.143(2)
1.942(2)
2.4766(8)
2.4529(9)
2.207(2)
2.068(2)
1.332(3)
2.4483(8)
2.4853(9)
2.198(2)
2.096(2)
1.324(3)
1.238(3)
1.336(4)
N(1)-Zn(1)-O(1)
N(2)-Zn(1)-O(1)
O(1)-Zn(1)-S(1)
O(1)-Zn(1)-S(2)
S(1)-Zn(1)-S(2)
N(2)-Zn(1)-S(1)
N(2)-Zn(1)-S(2)
N(2)-Zn(1)-O(2)•2
O(2)•2-Zn(1)-S(1)
O(2)•2-Zn(1)-S(2)
N(1)-Zn(1)-N(2)
N(1)-Zn(1)-S(1)
N(1)-Zn(1)-S(2)
N(1)-Zn(1)-O(2)•2
178.49(9)
99.99(9)
95.51(7)
96.51(7)
113.15(3)
130.54(7)
111.30(7)
172.13(8)
97.73(8)
91.83(6)
102.07(6)
98.42(3)
103.20(8)
150.05(6)
81.91(8)
172.98(6)
75.12(5)
79.42(8)
81.76(6)
83.48(6)
94.61(8)
175.60(9)
98.21(9)
100.10(7)
94.81(8)
108.27(3)
116.29(7)
130.15(7)
80.54(9)
83.09(6)
84.58(6)
80.36(9)
84.24(7)
83.07(7)
complex will not be discussed.13 A structural drawing of the
complex is available in the Supporting Information as Figure
S1. Three complexes (3, 5, and 6) of the aryloxide family
were characterized by X-ray crystallography. Details of the
data collection and structure refinement for these complexes
are given in Table 1. Selected bond distances and angles
are given in Table 2. Structural drawings are shown in
Figures 1 and 2.
In each zinc aryloxide structure, two nitrogen and two
sulfur donors from the bmnpa or benpa chelate ligand are
coordinated to the Zn(II) center. In 3 and 6, the aryloxide
ligand occupies a fifth coordination site, yielding a distorted
trigonal bipyramidal geometry (3, τ ) 0.80; 6, τ ) 0.76)20
Figure 1. ORTEP representation of the cationic portions of (a) [(bmnpa)-
Zn(OC6H4NO2)]ClO4 (3) and (b) [(benpa)Zn(OC6H4CN)]ClO4 (6). All
ellipsoids are shown at the 35% probability level (all hydrogen atoms except
the secondary amine hydrogen not shown for clarity).
for the cationic zinc center in each of these complexes. As
with other monomeric five-coordinate metal complexes of
the bmnpa ligand, two distinct N(py)-Zn-S(thioether)
angles are observed in 3 and 6 (3, N(2)-Zn(1)-S(1)
(20) Addison, A. W.; Rao, T. N.; Reedijk, J.; von Rijn, J.; Verschoor, G.
C. J. Chem. Soc., Dalton Trans. 1984, 1349-1356.
Inorganic Chemistry, Vol. 41, No. 13, 2002 3537

Garner et al.
Table 3. Distances (Å) and Angles (deg) of Hydrogen-Bonding
Interactions in 3, 5, and 6
3
5
6
N(3)‚‚‚O(1)
N(3)-H‚‚‚O(1)
2.775(3)
160(3)
2.776(3)
166(3)
2.777(4)
162(3)
Despite their differences in overall coordination number,
similar Zn-O(aryloxide) bond distances are observed for 3,
6 (av 1.946(2) Å) and 5 (1.962(2) Å). These distances only
slightly exceed those found in four-coordinate Zn-aryloxide
complexes (1.86-1.91 Å).11 The Zn-O(aldehyde) bond
length found in 5 (2.228(2) Å) is >0.10 Å longer than those
found in the octahedral [Zn(BA)4(ClO4)2] (av 2.06 Å), [Zn-
(BA)5(H2O)](BF4)2 (av 2.09 Å), and [Zn(BA)2(CH3CN)4]-
(BF4)2 (av 2.12 Å) complexes (BA ) benzaldehyde).21 In
these complexes, reported by Vahrenkamp et al., the Zn-
O(aldehyde) bond distances were influenced by the nature
of the coligands on the zinc center, with the longest Zn-
O(aldehyde) bonds being found when the remaining coor-
dination sites were occupied with increasing numbers of
water and acetonitrile ligands. The long Zn-O(aldehyde)
bond length in 5 (2.228(2) Å) is likely a consequence of the
presence of two sulfur donors in the equatorial plane, as well
as the weak donor properties of the aldehyde carbonyl group.
Consistent with the overall increase in coordination
number of 5, the Zn-S and Zn-N(py) distances of the
equatorial plane are elongated in 5 as compared to those
found for 3 and 6. Specifically, whereas the average Zn-S
distance in 3 and 6 is 2.466 Å, in 5 the average Zn-S
distance is 2.578 Å.
An important biomimetic feature of complexes 4-10 is
the presence of a single internal hydrogen bond donor in
the bmnpa/benpa supporting ligand systems (Table 3). In
complexes 3, 5, and 6, a similar hydrogen-bonding inter-
action, involving the donor N(3)-H and the acceptor O(1)
oxygen atom of the coordinated aryloxide ligand, is observed
for each complex. In general, these hydrogen-bonding
interactions are characterized by a N(3)‚‚‚O(1) distance of
∼2.78(1) Å and a N(3)-H(3)‚‚‚O(1) angle of ∼163(3)°.
These parameters are consistent with the classification of
these interactions as moderate hydrogen bonds.6 Comparison
of the hydrogen-bonding parameters found in these synthetic
complexes with those found in inhibitor-bound forms of
LADH (Table 4) indicates that the hydrogen-bonding
interactions in 4-10 are characterized by a heteroatom
distance that is generally similar to those found in the
biological system (typically ∼2.6 Å), when the resolution
of the protein crystal structures (1.8-2.5 Å) is taken into
consideration. We also note that the hydrogen-bonding
heteroatom distances found in 3, 5, and 6 are the shortest
found thus far for zinc complexes of the bmnpa and related
ligands.13,15 This is consistent with the greater negative charge
on the aryloxide oxygen in these complexes, as compared
to a neutral carbonyl oxygen donor (e.g., N,N-DMF),15
making the former a better hydrogen bond acceptor.
Figure 2. ORTEP representation of the coordination sphere of a single
zinc center (top) in the solid state chain structure (Chem3D representation)
of [(benpa)Zn(p-OC6H4CHO)]ClO4 (5) (bottom). The bridging aryloxide
groups that would extend the chain structure (bottom) from Zn(1)•2 and
Zn(1)•3 are omitted for clarity. All ellipsoids are shown at the 35%
probability level (all hydrogen atoms except the secondary amine and
aldehyde hydrogen not shown for clarity).
130.54(7)°, N(2)-Zn(1)-S(2), 111.30(7)°; 6, N(2)-Zn(1)-
S(1) 116.29(7)°, N(2)-Zn(1)-S(2), 130.15(7)°). Notably,
in both 3 and 6, the larger N(2)-Zn(1)-S angle does not
correspond to the location wherein the S-alkyl (Me or Et)
substituent is located. This positioning of the thioether alkyl
substituent in the area defined by the more acute N(2)-
Zn(1)-S angle of the equatorial plane is also observed in
[(bmnpa)Zn(ClO4)](ClO4).13 In each of these complexes, the
overall result of the difference in N(2)-Zn-S angles and
direction of thioether alkyl substituent canting is the genera-
tion of a potentially available sixth coordination position in
the equatorial plane. In 5, this coordination site is filled by
the aldehyde carbonyl oxygen of an aryloxide bound to
another zinc cation, resulting in an overall distorted octahe-
dral geometry for each Zn(II) ion and a chain-type structure.
The observed N(2)-Zn(1)-S angles in 5 reflect the change
in the metal ion geometry with a notable enlargement in one
N(2)-Zn(1)-S bond angle (N(2)-Zn(1)-S(2), 150.05(6)°)
and contraction in the other (N(2)-Zn(1)-S(1), 103.20(8)°).
The angles of the equatorial plane involving the aldehyde
carbonyl oxygen donor are acute (O(2)•Z-Zn(1)-N(2),
81.91(8)°; O(2)•Z-Zn(1)-S(2), 75.12(5)°).
FTIR Spectroscopy. Solid state and solution FTIR studies
of the zinc aryloxide complexes were undertaken in order
(21) Mu¨ller, B.; Vahrenkamp, H. Eur. J. Inorg. Chem. 1999, 117-127.
3538 Inorganic Chemistry, Vol. 41, No. 13, 2002

N/S-Ligated Zinc Aryloxide Complexes
Table 4. Comparison of Hydrogen-Bonding Interactions with LADH
Solid state FTIR spectra of 7 exhibit a νCdO stretching
vibration shifted to lower energy (1648 cm-1) as compared
to its position in solid state spectra of p-hydroxyacetophenone
(1663 cm-1). While this shift (15 cm-1) may indicate zinc
coordination of the ketone carbonyl oxygen in the solid state,
we speculate that it may be due instead to a decrease in
the electronic density of the aryloxide moiety as a whole,
resulting from zinc complexation of the deprotonated aryl-
oxide oxygen atom.22 We have developed this hypothesis
based on the results of solution FTIR studies of 7 in solvents
of differing donor properties. Specifically, in CH2Cl2 or CH3-
CN solution (∼100 mM), the νCdO vibration for 7 is found
at 1662 cm-1, still ∼13-14 cm-1 lower than that observed
for free p-hydroxyacetophenone under identical conditions
(∼100 mM CH2Cl2 solution, 1675 cm-1; ∼100 mM CH3-
CN solution, 1676 cm-1). As CH3CN may be anticipated to
be a better donor for the zinc cation than would be the ketone
carbonyl oxygen atom, it is unlikely that the shift observed
in both CH2Cl2 and CH3CN solution arises from a Zn-
carbonyl oxygen interaction. At this point, it is important to
distinguish the fact that this is not the case for the aldehyde-
appended aryloxide derivative 5, wherein the difference in
νCdO between 5 and p-hydroxybenzaldehyde in solid state
spectra is >40 cm-1. In solution spectra in CH2Cl2 or CH3-
CN, this difference drops to 5 and 10 cm-1, respectively,
indicating a more significant perturbation of the carbonyl
moiety of 5 in the solid state.
distance
(Å)
heteroatoms
N(3)‚‚‚O(1)
[(bmnpa)Zn(OC4H4CHO)]ClO4 (5) N(3)‚‚‚O(1)
[(bmnpa)Zn(OC6H4NO2)]ClO4 (3)
2.775(3)
2.776(3)
2.777(4)
2.93a
[(bmnpa)Zn(OC6H4CN)]ClO4 (6)
[(bmnpa)Zn(OClO3)]ClO4
N(3)‚‚‚O(1)
N(3)‚‚‚O(1)
N(1)‚‚‚O(1)
[(bmapa)Zn(N,N-DMF)](ClO4)2
2.86b
LADH (alkoxide: calcd)
LADH (DMSO inhibited; 1.8 Å)
O(Ser48)‚‚‚O(alkoxide)
O(Ser48)‚‚‚O(DMSO)
2.44c
2.6d
LADH (N-CyForm inhibited; 2.5 Å) O(Ser48)‚‚‚O(N-CyForm) 2.6e
LADH (N-FormPip inhibited; 2.5 Å) O(Ser48)‚‚‚O(N-FormPip) 2.5e
a Berreau, L. M.; Allred, R. A.; Makowska-Grzyska, M. M.; Arif, A.
M. Chem. Commun. 2000, 1423-1424. b bmapa ) N,N-bis-2-(methylthio)-
ethyl-N-(6-amino-2-pyridylmethyl)amine: Berreau, L. M.; Makowska-
Grzyska, M. M.; Arif, A. M. Inorg. Chem. 2001, 40, 2212-2213. c Agarwal,
P. K.; Webb, S. P.; Hammes-Schiffer, S. J. Am. Chem. Soc. 2000, 122,
4803-4812. d Al-Karadaghi, S.; Cedergren-Zeppezauer, E.; Ho¨vmoller,
S.; Petratos, K.; Terry, H.; Wilson, K. S. Acta Crystallogr. 1994, D50,
793-807. e N-CyForm ) N-cyclohexylformamide; N-FormPip ) N-formyl-
piperidine: Ramaswamy, S.; Scholze, M.; Plapp, B. V. Biochemistry 1997,
36, 3522-3527.
to correlate their X-ray crystallographically determined
structures with their solution behavior and to more fully
understand the hydrogen-bonding interaction involving the
zinc-bound aryloxide oxygen atom and zinc-carbonyl
oxygen interactions in 5. For each aryloxide complex, the
N-H stretching vibration is broadened and shifted to lower
energy as compared to the free ligand, consistent with its
involvement in a hydrogen-bonding interaction in the solid
state in 3-10. Notably, in complex 5, the N-H stretching
vibration (3254 cm-1) is found ∼38 cm-1 higher than that
observed for 3, 4, 6, and 8-10 (av 3216 cm-1). The shift to
higher energy in 5 is likely due to electronic perturbation of
the aryl ring induced by coordination of the carbonyl oxygen
to a second zinc center, as is observed in the solid state
structure of 5. This coordination will withdraw electron
density from the ring, making the aryloxide oxygen less
electron rich and therefore a poorer hydrogen bond acceptor.
The net result is an N-H bond strength in 5 that is closer to
that of the free ligand (3400 cm-1) than that of the zinc
aryloxide derivatives wherein coordination to a second zinc
center does not occur.
The aryl carbon-O(1) stretching vibration (νC-O) in
complexes 3-10 is found in the region of 1260-1305 cm-1,
with those possessing a para-electron-withdrawing group
found at ≈ 1279 cm-1 (3-8) and the complex which
possesses a para-electron-donating group (10) at 1261 cm-1.
1
1H and 13C NMR. The H NMR spectroscopic features
(Table S3) of 4-10 are similar, indicating that the solution
structures of these complexes are quite comparable. For
1
example, 4 exhibits H NMR spectral features in CD3CN
solution that are generally similar to those observed for 5.
Coupled with the solution FTIR studies of 5 in CH3CN
solution (vide supra), this indicates that the chain structure
observed in the solid state for 5 is cleaved in CH3CN
solution. With the exception of the chemical shift of the
secondary amine proton, the chemical shifts of the aryl and
alkyl protons of the benpa ligand vary only slightly in 4-10.
For example, the singlet resonance observed for the benzylic
protons in 4-10 is found at 3.87 ( 0.04 ppm.
The chemical shift of the secondary amine proton (N(3)-
H) in 3-10 can be correlated with the pKa of the parent
phenol (Figure 3). This is exemplified by comparing the
chemical shift of the N-H proton for 4 (8.93 ppm; pKa
p-nitrophenol ) 7.14) with that of 10 (9.97 ppm; pKa
p-methoxyphenol ) 10.2). The downfield shift of the
N(3)-H resonance in 10 indicates that a stronger hydrogen-
bonding interaction is present in this complex, resulting from
the increased basicity of the aryloxide moiety.6
Solid state FTIR spectra of p-hydroxybenzaldehyde indi-
cate a νCdO at 1666 cm-1. As the region of 2000-1625 cm-1
in solid state FTIR spectra of 5 does not contain any
vibrations of even weak intensity, a carbonyl stretching
vibration (νCdO) could not be readily identified for this
complex. This indicates that νCdO in 5 is likely shifted to
lower energy and located beneath another medium/strong
vibration associated with the pyridine ring of the ligand in
the region of 1600-1630 cm-1. In CH2Cl2 (∼100 mM), 5
exhibits a νCdO vibration at 1685 cm-1 whereas the carbonyl
stretching vibration for free p-hydroxybenzaldehyde is found
at 1689 cm-1. Generally similar results are obtained in CH3-
CN solution (νCdO: 5, 1680 cm-1; p-hydroxylbenzaldehyde,
1690 cm-1). This indicates that the chain-type structure
observed in the solid state for 5 likely breaks apart in CH2-
Cl2 and CH3CN solution via cleavage of the intermolecular
Zn-O(aldehyde) interactions.
(22) (a) Mu¨ller, B.; Vahrenkamp, H. Eur. J. Inorg. Chem. 1999, 129-
135. (b) Mu¨ller, B.; Vahrenkamp, H. Eur. J. Inorg. Chem. 1999, 137-
144.
Inorganic Chemistry, Vol. 41, No. 13, 2002 3539

Garner et al.
hydrolysis reactions at 300 K revealed that formation of a
zinc aryloxide derivative was favored by incorporation of a
para-electron-withdrawing substituent on the aromatic ring.
Additional research by Parkin et al. revealed that
mononuclear alkoxide complexes of the general formula
TptBu,MeZn-OR are also thermodynamically unstable with
respect to hydrolysis, forming equilibrium mixtures in the
presence of water that lie significantly toward the hydroxide
derivative (TptBu,MeZn-OH).11e On the basis of these results,
the zinc alkoxide intermediate that is proposed to form during
the catalytic cycle of LADH would be expected to be very
unstable with respect to hydrolysis, unless structural or
electronic features (e.g., hydrogen-bonding involving Ser48,
a mixed nitrogen/sulfur ligand environment) within the active
site of the enzyme in some way promote alkoxide formation.
The family of zinc aryloxide complexes reported herein
was prepared in order to initiate investigations into how
properties of the active site of LADH influence the chemistry
of a zinc-bound deprotonated alcohol ligand. In particular,
we are interested in the effect of hydrogen-bonding on the
thermodynamic stability of zinc alkoxide species with re-
spect to hydrolysis. As described herein, synthesis of this
family of nitrogen/sulfur-ligated zinc aryloxide complexes
was achieved starting from the zinc hydroxide precursors
[(bmnpaZn)2(µ-OH)2](ClO4)2 or [(benpaZn)2(µ-OH)2](ClO4)2.
Use of excess molar equivalents of the respective aryl alcohol
was necessary in order to avoid isolation of mixtures of the
desired aryloxide complex and its hydroxide precursor,
suggesting that equilibria involving the water produced in
the reaction are likely present in these systems. Future work
will be directed at delineating how the presence of a single
internal hydrogen bond donor, the mixed N/S-coordination
environment, and the electronic properties of the zinc-bound
aryloxide influence zinc hydroxide/aryloxide equilibria. That
being said, an approach currently being pursued in our
laboratory toward examining the effect of a single hydrogen-
bonding interaction on the chemistry of N/S-ligated zinc
aryloxide species involves the construction and examination
of the hydrolytic properties of an analogous family of zinc
aryloxide complexes supported by the structurally related
N,N-bis-2-(methylthio)ethyl-N-(2-pyridylmethyl)amine (bmpa)
ligand.23
Figure 3. Correlation of chemical shift of N(3)-H proton resonance of
3-10 (dry CD3CN solution, 20(1) °C) with pKa of parent aryl alcohol.
The 13C NMR data (Table S4) of 3-10 display substantial
variability only in the chemical shift of the carbons of their
respective aryloxide ring. The carbonyl carbon 13C reso-
nances for 5 and 7 are found at 191.3 and 197.1 ppm,
respectively. These chemical shifts are very similar to those
found in the free aryl alcohols (192.1 and 197.8 ppm,
respectively), indicating little perturbation of the electron
density in the carbonyl unit for the zinc-bound aryloxide in
CD3CN solution. This result further suggests that the
aldehyde oxygen in 5 is not retained as a zinc ligand in CD3-
CN solution.
Discussion
Preparation of synthetic complexes relevant to species
proposed to occur in the catalytic cycle of LADH has been
the goal of a number of previous synthetic investiga-
tions.7,8c,10b,11,12 Of particular interest has been the generation
of mononuclear zinc complexes possessing a single depro-
tonated alcohol ligand, species relevant to the proposed active
form of LADH. Notably, previous studies by Vahrenkamp
et al. yielded structurally characterized examples of tetra-
hedral nitrogen-ligated zinc aryloxide complexes.11b These
complexes, which possess a supporting tris(pyrazolyl)-
hydroborato ligand, were generated upon reaction of a zinc
hydroxide precursor (TpCum,MeZn-OH, TpPh,MeZn-OH, or
TptBu,MeZn-OH) with the appropriate aryl alcohol (phenol,
p-nitrophenol, 2-hydroxy-3-methoxybenzaldehyde (o-vanil-
lin), 2-hydroxybenzyl alcohol (salicylic alcohol), 2,6-bis-
(hydroxymethyl)-p-cresol).11b In all cases, the TpR,RZn-OAr
derivatives were prepared under stoichiometric reaction
conditions in yields >50%, albeit those prepared from the
most acidic alcohol (p-nitrophenol) were isolated in the
highest yields (83-89%). A structurally related family of
mononuclear zinc aryloxide complexes of the general formula
TptBu,MeZn-(p-OC6H4X) (X ) NO2, C(O)CH3, C(O)OCH3,
I, H, CH3, tBu, OCH3) has been reported by Parkin et al.11e
In this case, all of the aryloxide derivatives were prepared
from reaction of a zinc hydride precursor (TptBu,MeZn-H)
and the appropriate aryl alcohol. This was necessary be-
cause the aryloxide complexes (TptBu,MeZn-(p-OC6H4X) are
thermodynamically unstable with respect to hydrolysis,
forming equilibrium mixtures with the hydroxide derivative
TptBu,MeZn-OH and free aryl alcohol in the presence of
water. Determination of the equilibrium constants of these
An important component of accurate model systems for
the active site zinc ion in LADH is the use of ligands that
provide a mixed nitrogen/sulfur coordination environment,
preferably involving thiolate donors in order to mimic the
electronic character of coordinated cysteine residues. Ideally,
these complexes would also demonstrate reactivity properties
pertinent to the enzyme. The ligands employed herein provide
an N2S2 coordination environment involving thioether sulfur
donors. While the presence of neutral thioether sulfur donors
in these complexes may be anticipated to produce a zinc
center that is more Lewis acidic than the active site zinc ion
in LADH, this may be tempered to some degree by the
presence of an additional nitrogen donor. Therefore, while
(23) Ambundo, E. A.; Deydier, M.-V.; Grall, A. J.; Aguera-Vega, N.;
Dressel, L. T.; Cooper, T. H.; Heeg, M. J. Orchrymowicz, L. A.;
Rorabacher, D. B. Inorg. Chem. 1999, 38, 4233-4242.
3540 Inorganic Chemistry, Vol. 41, No. 13, 2002

N/S-Ligated Zinc Aryloxide Complexes
these complexes are not perfect structural models for the
proposed active species formed in the catalytic cycle of
LADH, they will enable the first opportunity to systemati-
cally examine the hydrolytic reactivity of nitrogen/sulfur-
ligated zinc aryloxide species possessing a single internal
hydrogen bond donor. Efforts are also underway to modify
the ligand systems utilized herein to include thiolate donors,
so as to be able to directly examine the chemical effect of
neutral versus anionic sulfur ligation. In this regard, to our
knowledge, only one thiolate-ligated zinc aryloxide complex
has been previously reported ([Zn(L3S)(OPhp-NO2)], where
L3S ) bis(3,5-dimethylpyrazolyl)(1-methyl-1-sulfanylethyl)-
methane), albeit its solid state structure was not elucidated
by X-ray crystallography.11f
The preparation and characterization of this particular
family of zinc aryloxide complexes has enabled an initial
evaluation of how a single hydrogen-bonding interaction
involving a zinc-bound deprotonated alcohol ligand is
perturbed upon changes in the basicity of the alcoholate
moiety. As outlined in Figure 3, we have discovered that
deshielding of the N-H resonance in these complexes can
be correlated with increasing pKa of the parent aryl alcohol.
This result suggests that the hydrogen-bonding interaction
involving the zinc-bound aryloxide ligand is becoming
stronger as the aryloxide fragment increases in basicity.6
While the structurally characterized aryloxide complexes
reported herein do not reveal differences in hydrogen-
bonding heteroatom distances, it must be noted that 3, 5,
and 6 are derived from aryl alcohols found in a very narrow
pKa range (7.15-7.95, as measured in water). Therefore, an
important future goal is structural characterization of zinc
aryloxide complexes derived from higher pKa aryl alcohols
and, more importantly, zinc alkoxide derivatives. In regard
to LADH, these results suggest that the strength of the
hydrogen-bonding interaction between Ser48 and a zinc-bound
alkoxide may be modulated by changes in the basicity of
the alkoxide.
Concluding Remarks
The mononuclear zinc aryloxide complexes reported herein
demonstrate the feasibility of the bmnpa/benpa ligand
frameworks for supporting nitrogen/sulfur-ligated zinc com-
plexes possessing a single deprotonated alcohol ligand. These
complexes are relevant to the proposed active form of LADH.
The inclusion of a single internal hydrogen bond donor in
3-10 mimics the proposed active site secondary hydrogen-
bonding interaction involving Ser48 and a zinc-bound alkox-
ide in the enzyme. As suggested by Plapp2 and Hammes-
Schiffer,3 and reiterated by Parkin,11e hydrogen bonding may
play a key role in stabilization of the zinc alkoxide
intermediate in LADH. That being said, this work provides
the foundation for future reactivity studies directed at
elucidating the effect of hydrogen-bonding on the chemistry
of nitrogen/sulfur-ligated zinc aryloxide species.
Acknowledgment. We acknowledge the support of the
donors of the Petroleum Research Fund (ACS-PRF 36394-
G3), administered by the American Chemical Society, and
the National Science Foundation (CAREER Award CHE-
0094066). We also thank Magdalena M. Makowska-Grzyska
for technical assistance and valuable discussions and the
reviewers for helpful comments.
Supporting Information Available: X-ray crystallographic
files, in CIF format, for the structure determinations of 2, 3, 5 and
6. An ORTEP diagram (Figure S1) of the cationic portion of
[(benpaZn)2(µ-OH)2](ClO4)2 (2) and tables outlining the details of
X-ray data collection and refinement for 2 (Table S1) and
comparison of bond distances and angles between [(bmnpaZn)2-
(µ-OH)2](ClO4)2 (1) and 2 (Table S2). Tables of 1H and 13C NMR
data (Tables S3 and S4) for complexes 1-10. This material is
available free of charge via the Internet at http://pubs.acs.org.
IC020031Q
Inorganic Chemistry, Vol. 41, No. 13, 2002 3541