Contribution of intramolecular NH...O hydrogen bonds to magnesium-carboxylate bonds

Article abstract of DOI:10.1021/ic400671v

A series of magnesium carboxylate complexes containing intramolecular NH...O hydrogen bonds were synthesized. Their molecular structures were determined by X-ray analysis. A direct NH...O hydrogen bond to the coordinated oxygen atom elongated the Mg-O bond, while a hydrogen bond to the carbonyl group shortened the Mg-O bond. Double NH...O hydrogen bonds significantly lowered the basicity of the carboxylate anion and prevented coordination to the Mg ion in a trans configuration; however, a cis-dicarboxylate complex was successfully obtained. Strong coordination of water to the Mg²⁺ ion stabilizes the weak Mg-carboxylate bond at the trans position. In contrast, a weak Mg-carboxylate bond strengthens the Mg-O(water) bond, probably increasing the acidity. Based on the experimental results and theoretical calculations, a new switching mechanism is proposed. In the proposed mechanism, the acidity of the coordinated water on magnesium is controlled during catalytic hydrolysis in endonuclease.

Full text of DOI:10.1021/ic400671v

Article
pubs.acs.org/IC
Contribution of Intramolecular NH···O Hydrogen Bonds to
Magnesium−Carboxylate Bonds
Taka-aki Okamura* and Junko Nakagawa
Department of Macromolecular Science, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
S
* Supporting Information
ABSTRACT: A series of magnesium carboxylate complexes
containing intramolecular NH···O hydrogen bonds were synthe-
sized. Their molecular structures were determined by X-ray analysis.
A direct NH···O hydrogen bond to the coordinated oxygen atom
elongated the Mg−O bond, while a hydrogen bond to the carbonyl
group shortened the Mg−O bond. Double NH···O hydrogen bonds
significantly lowered the basicity of the carboxylate anion and
prevented coordination to the Mg ion in a trans configuration;
however, a cis-dicarboxylate complex was successfully obtained.
Strong coordination of water to the Mg2+ ion stabilizes the weak
Mg−carboxylate bond at the trans position. In contrast, a weak Mg−
carboxylate bond strengthens the Mg−O(water) bond, probably
increasing the acidity. Based on the experimental results and
theoretical calculations, a new switching mechanism is proposed. In the proposed mechanism, the acidity of the coordinated
water on magnesium is controlled during catalytic hydrolysis in endonuclease.
INTRODUCTION
■
Magnesium is widely distributed in seawater and soil and is a
biologically essential element, playing very important roles in a
wide range of enzymes in most living organisms. The major
families of enzymes that use magnesium include kinase, ligase,
and phosphatase. They are related to the phosphorylated
compounds used in energy metabolism or storage of genetic
information.1 These are the key enzymes in the life cycles of
cells and viruses deeply associated with serious diseases and
Figure 1. Schematic drawing of the active site of endonuclease
repair of damaged DNA; e.g., a human immunodeficiency virus
EcoRV−substrate complex with the Mg2+ ion (PDB ID: 1RVB).5
type I (HIV-1) integrase,2 an avian influenza polymerase
(PAN),3 DNA mismatch repair protein (MutS),4 type II
restriction endonuclease EcoRV,5 and related enzymes.6
different chemistry from the fourth-row elements, especially
These enzymes are activated by the addition of the Mg ion
or a similar divalent metal ion (Mn2+), depending on the
concentration.7 The coordination environment of biological
magnesium complexes in enzymes has been described as a
normal octahedral geometry with six-coordination around the
Mg site, although some exceptions also exist.8 The rigid
coordination geometry is probably caused by the limited
hybridization of s and p orbitals without the d orbital. A
schematic drawing of the active site of endonuclease EcoRV5 is
shown in Figure 1. In the hydrolysis of the phosphodiester
group, a water molecule or deprotonated hydroxide anion
should attack the ester. The catalytic chemistry of magnesium-
dependent enzymes has been described in the reviews.9,10 The
Mg ion acts as a Lewis acid to activate the bound substrate or
water molecule and/or stabilizes the active species. The Mg ion
affects the substrate directly (inner-sphere) or via water of
hydration (outer sphere). Ionic or labile Mg−O bond shows
inert complexes. Hydrated chromium(III) effectively lowers the
pKa of the bound water to give Cr−OH− species; however, the
concentration of Mg−OH− species is low, which unlikely acts
as a nucleophile by inner-sphere pathway.11 Obviously, the
intramolecular direct attack to the neighboring phosphodiester
is geometrically unfavorable and, therefore, improbable. It is
reasonable that the Mg−OH− species is readily protonated by
outer-sphere water to give free OH−.
Although the Mg ion is necessary to fix the substrate for site-
specific cleavage, deprotonation of a water molecule bound to
the Mg ion is one of the most plausible activation mechanisms
described for the related zinc enzymes.12,13 In the outer-sphere
mechanism, the magnesium-bound OH− generates a free
hydroxide nucleophile by the deprotonation of outer-sphere
Received: March 20, 2013
Published: September 11, 2013
© 2013 American Chemical Society
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Inorganic Chemistry
Article
water.10 Deprotonation of a water molecule on a Mg ion has
been described in detail by Glusker et al. The theoretical
calculations revealed that the presence of a Mg ion facilitates
the ionization of water; however, the intramolecular OH···O
hydrogen bond between water and carboxylate ligand does not
appreciably affect the pKa value.14 Ionization of water is
required to produce a nucleophile (OH−). Increasing the
acidity of water results in a weak conjugate base, according to
the fundamental acid−base chemistry; however, a strong base is
required for an effective nucleophilic attack. Assumption of a
switching mechanism solves the contradiction, or coexistence,
of a strong acid and base. Warshel et al. have proposed the
external OH− mechanism stabilized by Mg2+ ion based on
theoretical calculations, thereby eliminating the dilemma
mentioned above.15 Indeed, pH dependency of Mg2+-promoted
reaction in aqueous media suggests the importance of free OH−
under pH-controlled conditions.16 The question remains: How
is pH or the reactivity of the enzyme controlled in natural
systems? Moreover, theoretical interpretations of the exper-
imental data for the related reactions are sometimes difficult or
complicated.17,18 If such a switching mechanism exists, which
has never been proposed to our knowledge, the experimental
observation could be more reasonably interpreted. In this
Article, we explore the possibility of the regulation by hydrogen
bonds in the magnesium−carboxylate coordination chemistry.
In Figure 1, the NH···O hydrogen bond is found, along with
the OH···O hydrogen bond, which is the most favorable
candidate for the principal role in the switching mechanism.
Systematic investigations of NH···X (X = O, S, Se) hydrogen
bonds to the coordinated X to metal ion (M) have revealed
significant stabilization of the M−X bond.19 At first, the effect
of NH···S hydrogen bond to the covalent M−S (thiolate) bond
was described.20,21 This bond was seen in iron−sulfur proteins
by crystallographic studies.22 The hydrogen bond affects the
covalent dπ−pπ interaction between the M (dπ) and S (pπ)
atoms. Moreover, recent works on dioxomolybdenum(VI)
complexes clearly indicated that the NH···S hydrogen bond
stabilized a detached MoO bond via trans influence.23−25
The study was extended to the more-covalent M−Se
(selenolate)26 and more-ionic M−O (carboxylate,27 phos-
phate28) bonds. Interestingly, an NH···O hydrogen bond
stabilized a Ca−O (carboxylate, phosphate) bond, which was
believed to be ionic, by significant contribution of dπ−pπ
interaction. This has been established both experimentally and
theoretically, even though the d-orbital of the Ca2+ ion is
formally vacant.19,28 In the case of magnesium carboxylate, the
d-orbital has an energy level that is too high to be used, making
it unnecessary to consider the dπ−pπ interaction.
Chart 1. Carboxylate Ligands Containing NH···O Hydrogen
Bonds
EXPERIMENTAL SECTION
■
Materials. 2-CH3CONHC6H4COOH (L1) was obtained from
Aldrich, and purified by recrystallization. 2,6-(RCONH)2C6H3COOH
(R = CH3 (L3), t-Bu (L5)) was prepared by the literature
procedure.30,31
2-CF3CONHC6H4COOH (L2). To a tetrahydrofuran (THF) solution
(10 mL) of 2-aminobenzoic acid (1.87 g, 16.6 mmol) was added
trifluoroacetic anhydride (2.4 mL, 17.3 mmol) at 0 °C. After stirring
overnight at room temperature, the solution was concentrated under
reduced pressure to give a white powder. The residue was dissolved in
ethyl acetate, washed with saturated NaCl aqueous solution, and dried
over Na2SO4. After evaporation, the residual powder was recrystallized
from diethyl ether/n-hexane to give colorless plates. Yield: 1.60 g
1
(41.4%). H NMR (CDCl3): δ12.2 (1H, s), 8.67 (1H, d), 8.15 (1H,
d), 7.65 (1H, t). 7.24 (1H, t). ESI-MS (methanol solution, negative
mode): m/z 232.0 (M−H+, calcd. 232.0), 487.1 (2M−2H++Na+, calcd.
487.0), 736.0 (3M−2H++K+, calcd. 736.0), 990.9 (4M−3H++Na++K+,
calcd. 991.0). Anal. Calcd for C9H6F3NO3: C, 46.36; H, 2.59; N, 6.01.
Found: C, 46.00; H, 2.55; N, 6.21.
2,6-(CF3CONH)2C6H3COOH (L4). This compound was synthesized
by a similar method described in the report.30 To a solution of 2,6-
diaminotoluene (3.3 g, 27 mmol) in THF (40 mL) was added
dropwise trifluoroacetic anhydride (10 mL, 70 mmol) cooling in an ice
bath. After stirring overnight, volatile materials were removed under
reduced pressure. Water was added to the resulting residue. The solid
was filtered off, washed with a 2% HCl aqueous solution, water, 4%
NaHCO3 aqueous solution, and water, successively. The crude
product was recrystallized from ethyl acetate. The product was
collected with filtration, washed with diethyl ether, and dried over
P2O5 in vacuo to give 2,6-(CF3CONH)2C6H3CH3 in 90% yield. This
compound (7.0 g, 22 mmol), MgSO4 (2.7 g, 22 mmol), and KMnO4
(7.0 g, 44 mmol) were suspended in water (300 mL). The mixture was
stirred at 60 °C for 3 h and at room temperature overnight. Insoluble
materials were filtered out. The filtrate was acidified by concentrated
HCl to afford white solid, which was collected with filtration, washed
with water, and dried over P2O5 under reduced pressure. Yield: 0.19 g
(2.5%). 1H NMR (CDCl3): δ11.38 (2H, s), 8.45(2H, d), 7.69 (1H, t).
Anal. Calcd for C11H6F6N2O4: C, 38.39; H, 1.76; N, 8.14. Found: C,
38.33; H, 1.70; N, 8.26.
This compound was also synthesized by acylation of 2,6-
diaminobenzoic acid using trifluoroacetic anhydride in a similar
method described below to afford the product in 51% yield based on
the amine.
2,6-(n-BuCONH)2C6H3COOH (L6). 2,6-(CH3CONH)2C6H3COOH
(L3) (1.27 g, 5.35 mmol) was suspended in a 10% HCl aqueous
solution (170 mL). After stirring for 30 min at 90 °C, the suspension
changed to a pale yellow solution. This solution was dried in vacuo to
give a white powder, 2,6-(NH2)2C6H3COOH·2HCl. To the
suspension of the powder in CH2Cl2 (30 mL) was added triethylamine
(1.5 mL, 10.8 mmol); the mixture was cooled in an ice bath, and the
color of the mixture turned yellow. Valeryl chloride (1.3 mL, 10.9
mmol) was added carefully to the mixture cooling in an ice bath, and a
white powder was separated out immediately. After stirring overnight,
insoluble materials were removed by filtration, and the filtrate was
extracted with a 1 M NaOH aqueous solution. The aqueous layer was
acidified by concentrated HCl and extracted with ethyl acetate. The
organic layer was washed with a saturated NaCl aqueous solution and
then dried over Na2SO4. After the solvents were removed, the residual
In this Article, we describe the synthesis of magnesium
carboxylate complexes containing intramolecular NH···O
hydrogen bonds and the contribution of hydrogen bonds to
Mg−O bonds by X-ray analysis and theoretical calculations. An
intraligand OH···O hydrogen bond in magnesium salicylate has
already been reported.29 Two types of ligands, with single and
double intraligand NH···O hydrogen bonds, 2-
RCONHC6H4COOH (R = CH3 (L1), CF3 (L2)) and 2,6-
(RCONH)2C6H3COOH (R = CH3 (L3), CF3 (L4), t-Bu (L5),
n-Bu (L6)), were used; the deprotonated forms are shown in
Chart 1. Fortunately, a rare mononuclear carboxylate complex
in a cis-configuration was obtained by using L6.
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Article
oil was crystallized from diethyl ether/n-hexane to give a white
crystalline powder, which was recrystallized from ethyl acetate/n-
hexane. Yield: 0.303 g (17.6%). H NMR (CDCl3): δ9.82 (2H, s),
C34H60MgN4O15: C, 51.75; H, 7.66; N, 7.10. Found: C, 51.66; H,
7.58; N, 7.14.
1
[Mg{O2C-2,6-(n-BuCONH)2C6H3}2(H2O)2(CH3OH)2] (7). To a sol-
ution (1 mL) of Mg(OAc)2·4H2O (18.4 mg, 0.086 mmol) in methanol
was added a solution (1 mL) of L6 (54.9 mg, 0.171 mmol) in
methanol. After 5 days, colorless blocks were obtained by slow
evaporation of solvents at room temperature. Yield: 59.8 mg (91.5%).
Anal. Calcd for C36H58MgN4O12: C, 56.66; H, 7.66; N, 7.34. Found:
C, 56.26; H, 7.61; N, 7.38.
8.14 (2H, d), 7.49 (1H, t), 2.40 (4H, t), 1.70 (4H, quin), 1.39 (4H,
sex), 0.93 (6H, t). ESI-MS (methanol solution, negative mode): m/z
319.1 (M−H+, calcd. 319.2), 661.1 (2M−2H++Na+, calcd. 661.3).
Anal. Calcd for C17H24N2O4: C, 63.73; H, 7.55; N, 8.74. Found: C,
63.51; H, 7.48; N, 8.75.
[Mg(O2C-2-CH3CONHC6H4)2(H2O)4] (1). To a methanol/water
(1:1) solution (2 mL) of 2-CH3CONHC6H4COOH (L1) (142.5
mg, 0.80 mmol) was added a methanol/water (1:1) solution (1 mL) of
Mg(OAc)2·4H2O (86.3 mg, 0.40 mmol) at room temperature and the
solution was dried in vacuo. To the residue was added 2 mL of
methanol/water (1:1), and the solution was evaporated under reduced
pressure. This process was repeated several times to remove acetic acid
completely. The residue was recrystallized from hot water. Colorless
opaque plates were precipitated from the solution upon slow cooling
to room temperature. Yield: 96.3 mg (53.5%). Anal. Calcd for
C18H24MgN2O10: C, 47.76; H, 5.34; N, 6.19. Found: C, 47.83; H, 5.24;
N, 6.17.
[Mg(O2C-2-CF3CONHC6H4)2(CH3OH)4] (2). To a solution (1 mL) of
L2 (52.5 mg, 0.23 mmol) in methanol was added Mg(OAc)2·4H2O
(24.6 mg, 0.11 mmol) at room temperature and the solution was dried
in vacuo. To the oily residue was added 1 mL of methanol, and the
solution was evaporated to remove acetic acid completely. The oily
residue was washed with n-hexane to give a powder, which was
recrystallized from hot methanol. Colorless blocks were obtained by
slowly cooling the solution. Yield: 4.66 mg (5.9%). Anal. Calcd for
C22H26F6MgN2O10: C, 42.84; H, 4.25; N, 4.54. Found: C, 41.28; H,
4.06; N, 4.68.
[Mg(dmf)2(H2O)4][O2C-2,6-(CH3CONH)2C6H3]2 (3). Mg(OAc)2·
4H2O (44.9 mg, 0.209 mmol) and (NEt4)(OAc)·4H2O (108.3 mg,
0.413 mmol) was dissolved in a mixture of methanol and water (1:1)
(5 mL). L3 (199 mg, 0.841 mmol) was dissolved in the solution. After
evaporation of the solvents under reduced pressure, the resulting
residue was dissolved in acetonitrile. Diethyl ether was added to the
solution until the solution became turbid. After 2 weeks, brown solid
was obtained. This was hardly soluble in acetonitrile or methanol. The
solid was recrystallized from DMF/diethyl ether. After 1 week,
colorless plates were obtained. Yield: 12.7 mg (4.9%). Anal. Calcd for
C60H84MgN10O16: C, 47.17; H, 6.22; N, 11.79. Found: C, 47.14; H,
6.10; N, 11.83.
[Mg{2,6-(CH3CONH)2C6H3COO}2(H2O)4] (4). To a hot methanol
solution (5 mL) of Mg(OAc)2·4H2O (55.0 mg, 0.257 mmol) was
added L3 (123 mg, 0.519 mmol). A white precipitate was obtained
immediately. After decantation, the residue was dissolved in a mixture
of methanol and water (1:1). After 1 week, colorless blocks were
obtained by slow evaporation of solvents at room temperature. Yield:
34.0 mg (23.4%). Anal. Calcd for C22H30MgN4O10: C, 46.62; H, 5.33;
N, 9.88. Found: C, 46.48; H, 5.26; N, 9.87.
[Mg(CH3OH)6][O2C-2,6-(CF3CONH)2C6H3]2 (5). To a solution of
Mg(OAc)2·4H2O (43.0 mg, 0.200 mmol) in methanol (3 mL) was
added a solution of L4 (138 mg, 0.401 mmol) in methanol (2 mL),
and the solution was concentrated until the viscosity was increased.
After 1 day, some colorless crystals were obtained. Yield: 50.0 mg
(27.6%). Anal. Calcd for C28H34F12MgN4O14: C, 37.25; H, 3.80; N,
6.21. Found: C, 32.32; H, 2.68; N, 6.83. (Anal. Calcd for
[Mg(H2O)6][O2C-2,6-(CF3CONH)2C6H3]2: C, 32.27; H, 2.71; N,
6.84.) The results of X-ray analysis showed the presence of methanol,
but elemental analysis indicated replacement of the coordinated
methanol molecules by water.
[Mg(H2O)6][O2C-2,6-(t-BuCONH)2C6H3]2·H2O (6·H2O). Mg(OAc)2·
4H2O (54.7 mg, 0.255 mmol) and 2,6-(t-BuCONH)2C6H3COOH
(L5) (165 mg, 0.516 mmol) were mixed in 15 mL of ethanol and
warmed until it dissolved. After the removal of insoluble materials by
filtration, the filtrate was concentrated under reduced pressure. The
residue was dissolved in acetonitrile/methanol (2:1), and a drop of
water was added for crystallization. After 1 day, yellow blocks were
separated out. Yield: 56.0 mg (30.1%). Anal. Calcd for
[Mg(O2C-2-CH3CONHC6H4)(H2O)5][O2C-2-CH3CONHC6H4] (8).
This compound was synthesized in a similar method described for
1, except for recrystallization from boiling water. To a solution of L1
(0.432 g, 2.41 mmol) in methanol (5 mL) was added Mg(OAc)2·
4H2O (0.254 g, 1.18 mmol) to give a white precipitate immediately.
All solvents were removed under reduced pressure, and then the
residue was recrystallized from boiling water to afford pale-yellow
blocks. Yield: 0.295 g (52.9%). Anal. Calcd for C18H26MgN2O11: C,
45.93; H, 5.57; N, 5.95. Found: C, 45.90; H, 5.41; N, 5.94.
1
Physical Measurements. H nuclear magnetic spectroscopy (1H
NMR) spectra were obtained on a JEOL JNM-EX270 spectrometer,
using CDCl3 solution at 30 °C. Electron spin ionization-mass
spectroscopy (ESI-MS) spectra were taken on a Finnigan MAT
LCQ spectrometer, using methanol solution in positive and negative
modes.
X-ray Analysis. Each single crystal of compounds 1−8 was
mounted in a loop with Nujol. The X-ray data were collected at 200 K
on a Rigaku Raxis-RAPID Imaging Plate diffractometer with graphite
monochromated Mo Kα radiation (λ = 0.71075 Å). The structures
were solved via a direct method (SIR92,32 SHELXS-9733) and
expanded Fourier techniques using SHELXL-97.33 Non-hydrogen
atoms were refined anisotropically. H atoms of amide and OH groups
were found in the differential Fourier map, then located there, and
their coordinates were refined. Because the N−H distances in 8 did
not converge to reasonable values, these NH protons were treated as
riding models. The other H atoms were generated by the riding and
rotating model in SHELXL-97.
Density Functional Theory (DFT) Calculations. Geometry
optimizations and natural bond orbital (NBO) analysis were
performed using Becke’s three-parameter hybrid functionals
(B3LYP) in the Gaussian 03 program package,34 using the 6-
31+G** basis set. The initial structure of model A was constructed by
using internal coordinates based on the X-ray structure of [Mg(O2C-2-
CH3CONHC6H4)2(H2O)4] (1). The geometrical parameters of
model B are the same as those of model A, except for the use of
flipped aromatic ring about the phenyl−COO bond. For model C, the
amide groups of model A were replaced by H atoms with normal C−H
distance. The coordinates of 8 were used for the cationic initial model
D, [Mg(O2C-2-CH3CONHC6H4)(H2O)5]+. Analogous models E
(flipped aromatic ring) and F (without amide group) were derived
from D, as described above for A−C. Initial structures of cis-
coordinated models, cis-[Mg(O2C-2-CH3CONHC6H4)2(H2O)4] (G,
H, J) and cis-[Mg(O2CC6H5)2(H2O)4] (I), were prepared by some
modifications of the X-ray structure of [Mg{O2C-2,6-(n-Bu-
CONH)2C6H3}2(H2O)2(CH3OH)2] (7). The substituent groups
and methanol were replaced by suitable groups. The structures were
roughly optimized using the 3-21G* basis set and reoptimized by
using the higher-level basis set described above. The optimized
geometry was analyzed by MolStudio R4.0 (NEC Corp., Japan).
RESULTS
■
Synthesis. Magnesium complexes were synthesized using a
ligand-exchange reaction between magnesium acetate and the
corresponding carboxylic acid. Exhaustive evaporation of free
acetic acid under reduced pressure completed the reaction.
Trials of recrystallization using different solvents afforded
suitable crystals for the X-ray analysis. The products were
isolated as single crystals, resulting in relatively low yields. The
low solubility of the complexes in nonpolar solvents and the
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Article
Table 1. Crystallographic Data for Compounds 1−4
1
2
3
4
formula
fw
C18H24MgN2O10
452.70
C22H26F6MgN2O10
616.75
C28H44MgN6O14
712.99
monoclinic
P21/c
C22H30MgN4O12
566.80
cryst syst
space group
a (Å)
triclinic
monoclinic
C2/c
triclinic
P1
̅
P1
̅
6.7274(9)
9.090(1)
9.865(1)
111.785(3)
102.010(3)
95.572(3)
537.8(1)
1
22.358(2)
9.5203(7)
13.724(1)
90
14.285(1)
5.2966(5)
23.179(2)
90
7.581(2)
8.289(3)
11.245(4)
70.87(2)
75.99(2)
79.86(2)
644.1(3)
1
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
Z
dcalc (g cm−3
μ (mm−1
106.966(2)
90
100.963(7)
90
2793.5(4)
4
1721.8(3)
2
)
1.398
1.466
1.375
1.461
)
0.139
0.159
0.126
0.140
goodness of fit, GOF
1.13
1.14
1.02
1.05
a
R1 [I > 2σ(I)]
0.054
0.046
0.079
0.039
b
wR2 (all data)
0.162
0.138
0.218
0.102
a
b
2
2
R1 = ∑| |F0| − |Fc| |/∑|F0|. wR2 = {∑[w(F0 − Fc2)2]/∑[w(F0 )2]}1/2
.
Table 2. Crystallographic Data for Compounds 5−8
5
6·H2O
7
8
formula
fw
C28H34F12MgN4O14
902.88
C34H60MgN4O15
789.17
monoclinic
P21/c
C36H58MgN4O12
763.18
orthorhombic
Pbcn
C18H26MgN2O11
470.72
cryst syst
space group
a (Å)
triclinic
triclinic
P1
P1
̅
9.781(6)
10.393(7)
10.999(9)
102.82(3)
107.57(2)
112.72(2)
907(1)
1
12.241(3)
15.512(4)
27.609(7)
90
10.0683(8)
17.625(1)
23.070(2)
90
6.954(2)
14.566(7)
22.183(8)
100.40(1)
94.05(1)
101.22(1)
2154(5)
4
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
Z
dcalc (g cm−3
μ (mm−1
126.45(1)
90
90
90
4216(1)
4
4093.8(5)
4
)
1.652
1.243
1.238
1.451
)
0.183
0.110
0.106
0.146
goodness of fit, GOF
1.07
1.04
1.08
1.00
a
R1 [I > 2σ(I)]
0.055
0.047
0.068
0.060
b
wR2 (all data)
0.143
0.120
0.199
0.164
a
b
2
2
R1 = ∑| |F0| − |Fc| |/∑|F0|. wR2 = {∑[w(F0 − Fc2)2]/∑[w(F0 )2]}1/2
.
labile magnesium−carboxylate bonds prevented us from
determining the solution structures via NMR spectroscopy.
Evaluation of the strength of the NH···O hydrogen bonds failed
because only broad, overlapped, and complicated infrared (IR)
spectra were obtained in the ν(NH) and ν(OH) regions.
Therefore, the discussions in this report are limited to the
structural consideration using X-ray analysis and theoretical
calculations. Eight molecular structures were determined by X-
ray analysis and the crystallographic data are listed in Tables 1
and 2.
Structures of Magnesium Carboxylates Containing
Single NH···O Hydrogen Bond. Molecular structures of
[Mg(O2C-2-CH3CONHC6H4)2(H2O)4] (1) and [Mg(O2C-2-
CF3CONHC6H4)2(CH3OH)4] (2) are shown in Figure 2. H
atoms, except for those in the NH and OH groups, are omitted
for the sake of clarity. Red dotted lines represent possible NH···
O hydrogen bonds. These molecules were crystallized in a
centrosymmetric space group and each Mg ion was found on
an inversion center with mutually trans carboxylate ligands.
Figure 2. Molecular structures of (a) 1 and (b) 2.
Although the number of reported structures of mononuclear
magnesium dicarboxylates is very limited, a trans configuration
is typical for the analogous complexes; e.g., [Mg-
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(O2CCH3)2(H2O)4],35 [Mg(O2C-4-NO2C6H4)2(CH3OH)4],
and [Mg(O2C-4-CH3C6H4)2(CH3OH)4].36 The Mg ion re-
sides in the plane of the carboxylate group in a syn
conformation that is preferable to a stable bond.37
Interestingly, the modes of the intramolecular NH···O
hydrogen bonds in 1 and 2 are very different from each
other. In 1, the amide group (NH) is hydrogen-bonded to the
coordinated oxygen atom (O11). However, NH in 2 was
directed to the uncoordinated carbonyl oxygen atom (O12).
The two distinct hydrogen-bonding modes significantly
influenced the character of the Mg−O bond. Some selected
bond distances and angles are listed in Table 3. The Mg−O
Attempts to synthesize an anionic magnesium complex
analogous to the calcium derivatives failed and resulted in a
neutral and/or solvated complex. Such differences of the
coordination modes between Mg2+ and Ca2+ ions have already
been predicted using theoretical calculations of the protein
matrix by Lim et al., which shows Ca2+ ion prefers to bind to
the third carboxylate rather than bidentately but Mg2+ ion
chooses the formation of a hydrated neutral complex.40 All the
magnesium complexes in this Article contain two or less
carboxylate ligands with octahedral geometry. This tendency is
in good agreement with the reported systematic calcula-
tions.41−44 Magnesium acetate was mixed with four equivalents
of L3 in the presence of 2 equiv of (NEt4)(OAc), resulting in a
precipitate, which was recrystallized from DMF to give the
solvated compound [Mg(dmf)2(H2O)4][O2C-2,6-
(CH3CONH)2C6H3]2 (3). The molecular structure is shown
in Figure 3a, and geometrical parameters are listed in Table S2
Table 3. Selected Bond Distances and Bond Angles for 1 and
2
1
2
Bond Distances (Å)
Mg1−O11
Mg1−O2
Mg1−O3
mean Mg−O (water)
mean Mg−O (methanol)
C1−O11
C1−O12
N1−H1
2.073(2)
2.031(2)
2.067(2)
2.095(2)
2.071(2)
2.099(2)
2.085
2.081
1.270(3)
1.255(3)
0.88(3)
1.243(3)
1.89(3)
1.259(3)
1.268(3)
0.88(3)
1.224(3)
1.79(3)
C17O1
H1···O11 (O12)
Bond Angles (deg)
Mg1−O11−C1
N1−H1−O11 (O12)
129.8(2)
139(3)
134.0(2)
147(3)
(carboxylate) distances for [Mg(O2CCH3)2(H2O)4]35 and
[Mg(O2C-4-CH3C6H4)2(CH3OH)4]36 have been reported as
2.0761(8) and 2.061(2) Å, respectively. Considering these
distances, the Mg−O distance in 1 (2.073(2) Å) can be
considered as normal or slightly long. In contrast, 2 has a
significantly shorter Mg−O bond (2.031(2) Å). Similar NH···O
hydrogen bonds in the latter mode have been widely found in
the active sites of metalloproteins containing metal−carboxylate
bonds.3,5,38,39 These results suggest that hydrogen bonding to
the uncoordinated carbonyl oxygen stabilizes the Mg−O bond.
However, a direct hydrogen bond to the coordinated oxygen
decreases electron donation to the Mg ion, thus resulting in a
relatively weak Mg−O bond. The longer Mg−O bond and
smaller Mg−O−C angle in 1 indicate more p-character in the
O atom than in 2, suggesting that hybridization of s and p
orbitals was altered to supply an additional bond to the
neighboring NH group. All of the H atoms from the water
molecules were found in the differential Fourier map, whose
positions were then refined. The OH groups were intra-
molecularly or intermolecularly hydrogen-bonded to the
carbonyl O atoms.
Synthesis of Magnesium Complexes with Carboxylate
Containing Double NH···O Hydrogen Bonds. Benzoate
derivatives containing intramolecular double NH···O hydrogen
bonds and their calcium complexes have been reported in
previous papers.27,31 The molecular structure of 2,6-
(CH3CONH)2C6H3COOH (L3) with the crystallographic
data is shown in Figure S1 and Table S1 in the Supporting
Information. The structure resembles the one reported for 2,6-
(t-BuCONH)2C6H3COOH (L5), except for the presence of a
hydrogen bond from the acidic OH to the crystal water.
Figure 3. Molecular structures of (a) 3 and (b) 4.
in the Supporting Information. The Mg ion is coordinated to
two carbonyl groups of DMF and four water molecules. The
Mg−O (DMF) distance and Mg−OC angle are in the range
of the previously reported values.45,46 The deprotonated L3 is
not directly coordinated to the Mg ion; instead, it interacts with
the coordinated water via OH···O hydrogen bonds, which are
shown as blue dotted lines. The carboxylate anion forms
intramolecular double NH···O hydrogen bonds (red dotted
lines) and the carboxylate negative charge is delocalized in the
extended conjugated system of the amide carbonyl group. The
amide planes deviate from the benzene ring with torsion angles
of 48.1(6)° (around N1−C) and 20.0(7)° (around N2−C).
The carboxylate group is out of the plane of the aromatic ring
with a dihedral angle of −48.2(5)°. The lack of coplanarity
suggests that the hydrogen bonds are not very strong. The
complex apparently forms a soft acid−soft base structure
connected by hydrogen bond chains, where the hydrated Mg
ion behaves like a soft acid and the carboxylate acts as a weak
soft base.
When DMF was not used to avoid coordination, a neutral
compound, [Mg{2,6-(CH3CONH)2C6H3COO}2(H2O)4] (4),
was obtained. The molecular structure of 4 is shown in Figure
3b. Surprisingly, the amide carbonyl group of L3 was
coordinated to the Mg ion, disregarding the carboxylate
anion. Selected bond distances and angles are summarized in
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Table S3 in the Supporting Information. One (H1) of the two
protons of the amide groups is hydrogen-bonded to the
carboxylate oxygen (O11). The other NH (H2) is intermolec-
ularly hydrogen-bonded to O12. The relatively long Mg1−O1
distance (2.075(1) Å) and large Mg1−O1−C17 angle
(152.6(1)°) indicate an ionic bond character or the presence
of significant charge-transfer interaction.47 These results suggest
that the carboxylate ligand, with double NH···O hydrogen
bonds, acts as a soft base. Therefore, it would not coordinate
directly to a hard Mg ion. Such overwhelming coordination of
the amide group in the presence of a carboxylate ligand has
been shown only in a few reports.48,49 The mean distance of the
Mg−O (water) bonds is 2.049 Å, which is shorter than that of 1
(2.085 Å) and 3 (2.077 Å). These results indicate the donation
of water to the electron-deficient Mg ion is increased by the
small electron donation of the carbonyl ligand.
The deprotonated anion of L4 has a substantially planar
structure with the torsion angles of −2.2(4)° (around N1−C)
and 11.4(4)° (around N2−C), and it forms strong intra-
molecular NH···O hydrogen bonds with short H···O distances
(1.73(3) and 1.80(2) Å). Electron-withdrawing CF3 groups
increase the acidity of the NH proton, resulting in the
preferable strong hydrogen bonds. The electronegative CF3
groups form interionic CH···F interactions with the methyl
group of the coordinated methanol and intramolecular NH···F
hydrogen bonds. All the OH groups of methanol are hydrogen-
bonded with either the carboxylate anion (O3H···O11, O4H···
O12) or carbonyl group (O5H···O1). The equivalent C1−O11
and C1−O12 distances indicate a typical conjugated form of
the carboxylate anion. The conjugation is expanded to the
hydrogen bond chain, including the π-system of the amide
plane, O5−H···O1−C17−NH···O11···H−O3.
The reaction between magnesium acetate and another
carboxylic acid, 2,6-(CF3CONH)2C6H3COOH (L4) or L5,
gave salts of the fully solvated Mg ion and carboxylate anions.
The molecular structures, [Mg(CH3OH)6][O2C-2,6-
(CF3CONH)2C6H3]2 (5) and [Mg(H2O)6][O2C-2,6-(t-Bu-
CONH)2C6H3]2 (6), are shown in Figure 4. Selected bond
The coordinated water molecules are intermolecularly
hydrogen-bonded in the crystal of 6·H2O. The water molecules
are classified into four categories according to the number and
types of functional groups with which the molecules interact:
the first (O31) interacts with two carboxylate anions; the
second (O32, O33) interacts with one carboxylate anion and
one carbonyl group; the third (O34, O36) with two carbonyl
groups; and the fourth (O35) with two crystal water molecules.
The electron density of the coordinated oxygen atom is
probably increased by the formation of an OH···O hydrogen
bond with the electron-rich carboxylate anion, increasing the
basicity of the water ligand. Electron donation through the
hydrogen bond should follow the order of carboxylate >
carbonyl. This estimation is consistent with the observed result.
The Mg−O31 (2.014(1) Å) bond with two OH···O
(carboxylate) is the shortest. On the other hand, the Mg−
O32 (2.044(1) Å) and Mg−O33 (2.031(1) Å) bonds with one
OH···O (carboxylate) are significantly shorter than the other
Mg−O (2.081(1), 2.100(1) Å) bond. The mean Mg−O
(water) distance (2.062 Å) is significantly shorter than that of
1, which indicates that the coordination of carboxylate anion
increases the electron density on the Mg2+ ion resulting the
decrease of the donation from the aquo ligand.
Many trials to synthesize trans-bis(carboxylate) magnesium
complex using the doubly NH···O hydrogen-bonded carbox-
ylate ligands failed even if strictly dehydrated solvents were
used. This fact strongly suggests that the carboxylate anion with
double NH···O hydrogen bonds is unusually weak Lewis base.
Only one example with direct coordination of the ligand was
obtained, which is described below.
Structure of Cis-Coordinated Magnesium Carboxy-
late. The magnesium complex [Mg{O2C-2,6-(n-Bu-
CONH)2C6H3}2(H2O)2(CH3OH)2] (7) was successfully
obtained when 2,6-(n-BuCONH)2C6H3COOH (L6) was
used. The molecular structure is shown in Figure 5 and
selected geometrical parameters are listed in Table 4. The
molecule has a crystallographic 2-fold axis. Interestingly, two
carboxylate ligands are coordinated in the cis configuration.
Such a cis isomer is unusual for synthetic magnesium
carboxylates and previously has been seen only in chelate
compounds52−54 and catena structures.55−57 However, the cis
configuration is popular in biological systems.3,5,38 The n-butyl
chain is close to the benzoate moiety via intra- and
intermolecular CH···π interactions with short bond distances
(Cγ−H···C11 = 2.95 Å and Cα−H···C16 = 2.87 Å,
respectively). These stacking interactions probably stabilize
the cis configuration.
Figure 4. Molecular structures of (a) 5 and (b) 6.
distances and angles are listed in Tables S4 and S5 in the
Supporting Information. The carboxylate anions form intra-
molecular NH···O hydrogen bonds (red dotted lines) and
interionic OH···O hydrogen bonds (blue dotted lines) with the
OH group of the coordinated water or methanol. Two
carboxylate anions are located in the trans and cis configurations
for 5 and 6, respectively. Salts of [Mg(H2O)6]2+ with
carboxylate anions have been reported in both aliphatic50 and
aromatic51 carboxylates.
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Figure 5. Molecular structure of 7.
Table 4. Selected Bond Distances and Bond Angles for 7
Bond Distance Measurements
atom pair
bond distance
Mg1−O11
Mg1−O3
Mg1−O4
C1−O11
C1−O12
N1−H1
2.079(2) Å
2.038(3) Å
2.062(3) Å
1.268(4) Å
1.257(4) Å
0.82(4) Å
0.86(4) Å
1.220(5) Å
1.217(5) Å
1.89(5) Å
1.93(5) Å
N2−H2
C17O1
C27O2
H1···O11
H2···O12
Bond Angle Measurements
bond angle
value
Mg1−O11−C1
N1−H1−O11
N2−H2−O12
133.0(2)°
147(4)°
135(4)°
The relatively long Mg−O11 (2.079(2) Å) bond indicates
the low basicity of the carboxylate ligand, which is caused by
the double intramolecular NH···O hydrogen bonds (H1···O11
= 1.89(5) Å, H2···O12 = 1.93(5) Å). In contrast, the water
ligand at the trans position shows a short Mg−O3 bond
(2.038(3) Å). These results suggest that the strong
coordination of a water molecule alters a hard Mg ion to a
softer hydrated Mg ion. The softer ion then becomes more
attractive to the exceedingly soft doubly hydrogen-bonded
carboxylate ligand. From an opposite point of view, the doubly
hydrogen-bonded ligand strengthens the coordination of the
water molecule at the trans position.
Coordination of a Water Molecule Trans to the
Carboxylate Ligand. Recrystallization of 1 from boiling
water gave a partially hydrated compound [Mg(O2C-2-
CH3CONHC6H4)(H2O)5][O2C-2-CH3CONHC6H4] (8).
The molecular structure and crystal packing are shown in
Figure 6. Four molecules (1−4) were found in the asymmetric
unit, whose geometrical parameters are summarized in Table 5.
In comparison with 1, an additional water molecule was
coordinated in place of the carboxylate ligand, and the
dissociated anion was located nearby via OH···O hydrogen
bonds in 8. The position of the NH···O hydrogen bond is very
similar to that of 1, with regard to the coordinated carboxylate.
The geometrical parameters of molecules 1−4 either resemble
each other or are essentially identical. The Mg−O (carboxylate)
Figure 6. (a) Molecular structure for one (molecule 1) of the four
molecules of 8 in the asymmetric unit and (b) the crystal packing in
the unit cell.
distances of 8 are within the range 2.0472.050 Å and the
Mg−O−C angles are in the range 134.9°137.7°, which are
shorter distances and wider angles compared to 1. The Mg−O
(water) distance trans to the carboxylate ligand is 2.037 Å
(mean), which is comparable to 7. These results suggest that
strong coordination of water molecules strengthens the Mg−
carboxylate bond at the trans position. Similar contributions are
also seen in the structure of 7. The water ligand of 7 permits
the coordination of a very weakly basic, doubly hydrogen-
bonded carboxylate. In the case of 8, the water ligand
strengthens the slightly weak Mg−carboxylate bond to give a
normal bond. The mean Mg−O (water) distances (2.065
2.071 Å) are between those of 1 (2.085 Å) and 6 (2.062 Å),
which is simply interpreted as the dependence on the number
of carboxylate ligands.
DISCUSSION
■
Contribution of NH···O Hydrogen Bonds to Mg−O
Bonds. To determine the contribution of the NH···O
hydrogen bonds to the magnesium−carboxylate bonds found
in the structures of 1 and 2, theoretical calculations were done
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Table 5. Selected Bond Distances and Bond Angles for 8
molecule 1 (n = 1)
molecule 2 (n = 2)
molecule 3 (n = 3)
molecule 4 (n = 4)
Bond Distance Measurements
2.050(6) Å
Mgn−On1
2.049(6) Å
2.041(6) Å
2.077(6) Å
2.026(5) Å
2.092(6) Å
2.091(6) Å
2.065 Å
2.048(6) Å
2.039(6) Å
2.083(6) Å
2.088(6) Å
2.102(6) Å
2.031(7) Å
2.069 Å
2.047(6) Å
2.028(7) Å
2.078(6) Å
2.064(7) Å
2.092(6) Å
2.089(6) Å
2.070 Å
Mgn−On3 (trans)
Mgn−On4 (cis)
Mgn−On5 (cis)
Mgn−On6 (cis)
Mgn−On7 (cis)
mean Mg−O (warer)
Cn−On1
2.038(6) Å
2.076(6) Å
2.081(6) Å
2.087(6) Å
2.072(6) Å
2.071 Å
1.25(1) Å
1.284(9) Å
1.22(1) Å
1.92 Å
1.27(1) Å
1.27(1) Å
1.27(1) Å
1.22(1) Å
1.89 Å
1.29(1) Å
1.24(1) Å
1.23(1) Å
1.91 Å
Cn−On2
1.25(1) Å
Cn7On
1.22(1) Å
a
Hn···On1
1.91 Å
Bond Angle Measurements
135.5(5)°
Mgn−On1−Cn
Nn−Hn−On1
137.2(5)°
139°
135.2(6)°
139°
134.9(5)°
139°
a
138°
a
Nn−Hn = 0.88 Å (fixed).
using density functional theory (DFT). Based on the molecular
structure of 1, simplified centrosymmetric models, A−C, were
constructed, as shown in Figure 7a, and geometrically
Table 6. Geometric and Electrostatic Parameters of the
Optimized Structures of Models A−C
A
B
C
Mg−O2 (Å)
2.0614
0.1831
0.2785
2.0335
0.2021
0.3121
2.0434
0.1995
0.3173
a
bond index
b
bond order
Mg−O3 (Å)
bond index
bond order
2.1344
0.1509
0.2221
2.1666
0.1392
0.2252
2.1724
0.1375
0.2272
Mg−O4 (Å)
bond index
2.1408
0.1510
0.2200
2.1376
2.1057
0.1639
0.2619
2.1362
2.0998
0.1664
0.2681
2.1361
bond order
mean Mg−O (water)
C5−O2 (Å)
bond index
bond order
1.2891
1.3124
0.9897
1.2796
1.3373
1.0092
1.2846
1.3204
0.9971
C5−O6 (Å)
bond index
bond order
1.2721
1.4042
1.0291
1.2740
1.3977
1.0245
1.2610
1.4590
1.0444
H7···O2 (O6)
bond index
bond order
1.8001
0.0501
0.0666
1.7803
0.0567
0.0762
Mg−O2−C5 (deg)
123.91
133.64
130.37
natural charge
Mg
O2
O6
1.43187
1.42433
1.42581
Figure 7. (a) Schematic drawing of initial models A−C for the DFT
calculations. (b) Optimized structures of models A−C.
−0.82163
−0.77535
−0.81899
−0.76021
−0.83095
−0.72457
a
b
Wiberg bond index. Atom−atom overlap-weighted NAO bond
order.
optimized structures were obtained (Figure 7b). Isomeric
models, A and B, of [Mg(O2C-2-CH3CONHC6H4)2(H2O)4],
simulate the two modes of NH···O hydrogen bonds found in
structures 1 and 2, respectively. Model C is a nonsubstituted
benzoate complex, [Mg(O2CC6H5)2(H2O)4]. The calculated
geometric and electrostatic parameters are listed in Table 6.
The Wiberg bond index and atom−atom overlap-weighted
natural atomic orbital (NAO) bond order are shown in order to
estimate the covalency of the bond. For normal covalent bonds,
the bond index is approximately equal to the conventional bond
order. Positive values of atom−atom overlap-weighted NAO
bond order indicate a bonding character or an attractive
interaction between the two atoms.
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The Mg−O2 distances clearly show an elongation in A and
shortening in B, compared to C. Smaller (123.91°) and larger
(133.64°) Mg−O2−C5 angles are also found in A and B,
respectively, than that of C. These results are consistent with
the experimental results from X-ray analysis. Although the bond
lengths were in the expected order, the bond order was
reversed for B and C, that is, the short Mg−O2 bond does not
mean simply covalency. These results suggest that the
shortening of the bond length of Mg−O2 in B was caused
by another factor, which can be reasonably explained by
considering the contribution of donor−acceptor interaction
(i.e., delocalization of electrons). Second-order perturbative
estimates of the charge-transfer interaction58,59 from O2 to Mg
for A−C using NBO basis are shown in Table 7. The major
A (21.82). Small contributions from pπ(O) → pπ*(Mg)
donation show the following order: B (3.02) > A (2.52) > C
(2.49). The donation decreased both the negative charge on
O2 and the positive charge on Mg, as shown in Table 6.
The difference in the bond distances between C5−O2 and
C5−O6 of B is very small (0.0056 Å), indicating that the
resonance structure of the carboxylate moiety is likely in a
bidentate coordination mode. However, A and C show
significantly longer C5−O2 bonds. These results are consistent
with the observed structures of 2 and 1. The resonance
structure of the carboxylate anion is extended through the
entire ligand, including the NH···OC hydrogen bond, which
probably helped stabilize the relatively short Mg−O bond.
Influence of the Magnesium−Carboxylate Bond on
the Mg−O Bond at the Trans Position. Magnesium
bis(carboxylate) complexes are usually present as trans isomers
in crystal. As found in the structure of 1, a direct NH···O
hydrogen bond to the coordinated oxygen atom weakened the
Mg−O bond by decreasing the electron density on oxygen and
lowering the basicity of the ligand. Conversely, hydrogen bond
to the uncoordinated carbonyl oxygen shortened the Mg−O
bond. Introducing double hydrogen bonds to the carboxylate
ligand decreased the basicity of both the oxygen atoms,
resulting in weak coordination power; therefore, any
magnesium complex with such ligands could not be isolated
as a trans isomer. Fortunately, the coordination of such a weak
Lewis base was found solely in the cis configuration of 7. The
weak coordination of a doubly hydrogen-bonded carboxylate
ligand is supported by strong donation from a water molecule
at the trans position. Generally, the trans influence in
coordination complexes is attributed to transition-metal
complexes containing d-electrons and dπ−pπ interactions.23
In elements with only s and p electrons, such interaction has
rarely been considered, because of the limited orientation of
these orbitals. Instead, traditional hard and soft acid and base
(HSAB) theory is used. The Mg ion is a hard acid and prefers
hard bases, including ordinary carboxylate.60 When a water
molecule strongly coordinates to a naked Mg ion, the positive
charge on the ion spreads over the coordinated water, forming
a polarizable [Mg(H2O)m]2+ (1 ≤ m ≤ 6) ion. This ion
probably acts as a relatively soft acid. When m = 6, the Mg2+ ion
is a fully hydrated ion covered by H2O; thus, it never
coordinates directly to the carboxylate ligand, as found in 6.
When m = 5, one vacant site of the [Mg(H2O)5]2+ ion
accepts the carboxylate ligand with a normal Mg−O distance, as
seen in the crystal of 8. The Mg−O11 (carboxylate) bond is
shorter than that of 1 and the Mg−O13 (water) distance
(2.041(6) Å) at the trans position is relatively short among the
Mg−O (water) bonds (mean = 2.065 Å). These facts are
attributable to the trans influence, which was examined by
theoretical calculations. The initial modelsthe anion part of 8
(D), the flipped aromatic ring of D (E), and without the amide
group (F)were used for DFT calculations (see Figure 8).
The parameters obtained by geometry optimizations are listed
in Table S6 in the Supporting Information. The directly
hydrogen-bonded Mg−O2 bond of D (2.0275 Å) is longer than
those of E (2.0111 Å) and F (2.0171 Å), which is similar to the
tendency observed in models A−C in Table 6. However, the
difference between D and E (0.0164 Å) is smaller than that
between A and B (0.0279 Å). When comparing D and A, the
replacement of the carboxylate ligand with water clearly
shortened the Mg−O2 bond by 0.0339 Å, which is consistent
with the observation from the crystal structures. With regard to
Table 7. Second-Order Perturbative Estimates of Charge-
Transfer Interaction from O2 to Mg in the NBO Basis for
the Optimized Models A−C
donor NBO
a
hybrid acceptor NBO stabilization energy (kcal mol−1
)
total
Model A
nO
nO
sp3.72
s*Mg
p*Mg
24.89
28.40
53.29
sp1.43
s*Mg
p*Mg
p*Mg
6.86
12.64
2.32
21.82
57.68
24.07
56.39
23.88
nO
nO
p
p*Mg
2.52
Model B
sp2.66
s*Mg
p*Mg
27.39
30.29
nO
sp2.66
sp1.94
p*Mg
s*Mg
p*Mg
p*Mg
2.34
6.71
9.69
5.33
nO
nO
p
p*Mg
3.02
Model C
sp2.5
s*Mg
p*Mg
27.05
29.34
nO
sp2.5
sp1.98
p*Mg
s*Mg
p*Mg
p*Mg
3.95
5.73
8.21
5.99
nO
p
p*Mg
2.49
a
Selected energies were shown >2 kcal mol−1.
interactions nO → s*Mg and nO → p*Mg are found, which show
significant stabilization energy. When the molecules (or Mg−
O2 bonds) are placed along the z-axis (the vertical axis in
Figure 7), the dominant contribution comes from the filled pz-
rich hybrid on the oxygen atom (spn, n > 2) interacting with
vacant s* or pz* orbitals on the Mg ion. The delocalization of
electrons occurs along the O−Mg bond as σ-type donation.
The total stabilization energy (expressed in units of kcal mol−1)
ranks in the following order: B (57.68) > C (56.39) > A
(53.29). The other donations from the hybrid orbital are π-type
mixed with σ-type in the same order: B (24.07) > C (23.88) >
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Figure 8. (a) Schematic drawing of initial models D−F for the DFT
calculations. (b) Optimized structures of models D−F.
the Mg−O (water) bonds of D, shortening of the Mg−O bond
at the trans position could not be found. The mean Mg−O
(water) distances did not show significant difference among
models DF. The small differences of Mg−O2 and Mg−O
(water) among these model compounds suggest that the effect
of the hydrogen bonds is vague or weakened in the diffused
electronic density over the hydrated cation, [Mg(H2O)5]2+ (i.e.,
a soft Lewis acid).
Figure 9. (a) Schematic drawings of initial models G−J for the DFT
calculations. (b) Optimized structures of models G−J.
density on Mg2+, thereby decreasing acceptable electrons from
water. This behavior resembles the trans influence found in a
covalent metal−sulfur bond.23 Obvious elongation of the Mg−
O2 (carboxylate) bond and shortening of the Mg−O4 (water,
trans) bond were found in models G and J, when compared to
models H and I, although the Mg−O5 bond in G is long.
Interestingly, the unsymmetrical NH···O hydrogen bonds
provide uneven Mg−O (carboxylate) bonds with considerable
disparity (0.0472 Å), and a short Mg−O5 distance (2.1487 Å)
trans to a short Mg−O3 (2.0314 Å) was found, in addition to a
short Mg−O4 (2.1550 Å) trans to a long Mg−O2 (2.0786 Å).
The mean Mg−O (water) distance of J (2.1389 Å) is smaller
than the others (2.14702.1482 Å) and longer than those of
models DF (2.12052.1220 Å) with one carboxylate ligand.
The relatively small natural charge on Mg in J (1.43023)
indicates the total electron acceptance from the coordinated O
atoms, which is consistent with the shortening of Mg−O bonds.
For the other parameters, the tendency is similar to the
difference between A and B in Table 6. The direct NH···O
hydrogen bonding to the coordinated O atom results in a small
Mo−O−C angle. The hydrogen bond to a carbonyl group
shows a relatively large bond order and results in a resonance
structure of the carboxylate moiety.
Consequently, coordination of the carboxylate elongates or
weakens the Mg−O (water) bond at the trans position through
electron donation from the anionic oxygen of the carboxylate
ligand. The hydrogen bond interacts with an anionic oxygen
atom and decreases the negative charge on O by direct NH···
O− interaction or via the conjugated carboxylate anion such as
NH···OC−O−, which strengthens the Mg−O (water) bond.
The strength of the Mg−O (water) bond directly influences the
acidity of the water molecule. These results suggest a possible
mechanism to control the pKa of coordinated water via an
The successful coordination with double NH···O hydrogen
bonds of the weakly basic carboxylate ligand in 7 strongly
suggests the importance of the cis configuration. In order to
confirm the contribution of the NH···O hydrogen bonds, cis
configuration, and coordination of water, geometrical opti-
mizations were performed using simplified models. For DFT
calculations, a singly hydrogen-bonded ligand was used to
separate confused factors. The coordinates of 7 were used as a
model after some modifications such as the replacement of
methanol by water and the partial deletion of amide groups.
Four models were used: one with two NH···O hydrogen bonds
to the coordinated O atom (G), another with two NH···O
bonds to the other uncoordinated O atom (H), one without
NH···O bonds (I), and finally, an unsymmetrical structure with
the two types of NH···O (J) (see Figure 9). The obtained
geometric and electrostatic parameters are summarized in
Table S7 in the Supporting Information. In each of the models
GJ, the Mg−O4 and Mg−O5 bonds, at the positions trans to
the carboxylate, are longer than the other bonds (Mg−O6,
Mg−O7). This common tendency is likely because of the trans
influence, which is attributed to the contribution of charge
transfer or delocalization of electrons from the filled orbital on
O to the vacant one on Mg. The interaction is not necessarily
covalent, as found in soft base−soft acid coordination in
transition-metal complexes, and is closely related to the NBO
described above. The interactions in the Mg−O bond using
hybridization of sphere s and orthogonal p orbitals cause
competitive donation to Mg2+ along the linear O−Mg−O
bond. The anionic carboxylate ion increases the electron
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NH···O hydrogen bond and are described in the following
section. In the real protein, an intermolecular hydrogen bond
including the coordinated water possibly contributes to the
reactivity of the hydrolysis,10,11 although our isolated model
system did not take the possibility into account.
avian influenza polymerase.3 The imidazole nitrogen is located
close to the carboxylate ligand, suggesting the presence of a
potential (imidazole)NH···O hydrogen bond (N···O = 3.22,
3.82 Å), although NH is illustrated in the opposite direction.
Rotation and/or tautomerism of the imidazole group could act
as a switch. In magnesium-containing proteins, dinuclear or
trinuclear catalytic sites were found where the Mg ion plays the
role of a binding site for the substrate and/or a reactive
site.5,7,61 The μ-carboxylate bridged Mg−OCO−Mg structure
resembles the NH···OCO−Mg hydrogen bond. Our results
suggest that the Mg ion, or Lewis acid, acts like the NH group
in a hydrogen bond. Therefore, the concentration of the Mg2+
ion influences the catalytic activity as well as construction of the
binding site.7 In the mechanism of phosphatase activity, direct
attack of the Mg-binding carboxylate anion (Asp residue) to the
phosphate ester has also been proposed.39,62,63 The reaction
must be strictly dependent on the basicity of the carbonyl
group of Asp residue, with the hydrogen bond also contributing
significantly.
Biological Relevances of NH···O Hydrogen Bonds to
the Endonuclease Active Site. The contribution of a
carboxylate ion to the acidity of the coordinated water in a
magnesium complex has been described in a report by Glusker
et al.14 According to the calculation shown in the report, the
replacement of one H2O molecule of [Mg(H2O)6]2+ by a
carboxylate anion increases the energy of deprotonation by ∼80
kcal/mol. The observed elongation of the mean Mg−O (water)
distance by increasing the number of carboxylate ligands is
consistent with the literature, suggesting the decrease of the
acidity. The report also demonstrated that the most acidic
water in a [Mg(H2O)5(carboxylate)]+ ion is in the position
trans to the carboxylate ligand although the coordinated water
is less acidic than that in [Mg(H2O)6]2+. By combining the
results of the Glusker et al. report and our present work, a new
mechanism is proposed for the active site of endonuclease (see
Figure 10). A schematic drawing of the magnesium-binding site
CONCLUSIONS
■
The magnesium−carboxylate complexes containing intra-
molecular NH···O hydrogen bonds revealed significant
contributions to the bond character of the Mg−O linkage
(Figure 11). Direct NH···O hydrogen bonding to the
Figure 10. Proposed regulation mechanism of the acidity of the
coordinated water; acidic water induced by the NH···O hydrogen-
bonded carboxylate ligand (left) and hypothetical basic active site after
deprotonation (right), where the hydrogen bond is broken.
in endonuclease EcoRV is shown in Figure S2a in the
Supporting Information.5 In the magnesium site of endonu-
clease, the cis-carboxylate configuration is frequently found,
where a phosphodiester or phosphate (product) is bound to
the Mg ion at the position trans to the carboxylate ligand, as
shown in Figures 1 and 10, as well as in Figure S2a in the
Supporting Information. The carboxylate ligand forms an NH···
OC hydrogen bond with the NH on the peptide backbone,
which probably stabilizes the tight binding of the substrate, i.e.,
Mg−O−P bond. The carboxylate forming the NH···O
hydrogen bond weakly coordinates to Mg, strengthening the
Mg−O (water) bond in the trans position, thus increasing the
acidity of water (see Figure 10). The direct NH···O hydrogen
bond to the coordinated O is the most effective in increasing
the acidity of water. If the ligand forms double NH···O
hydrogen bonds, it is the best. Deprotonation of the acidic
water molecule gives the relatively weak conjugate base, Mg−
OH, according to the fundamental acid−base chemistry. If the
hydrogen bond is cleaved simultaneously or subsequently, the
basicity of the hydroxide group must increase dramatically (see
Figure 10). The basic OH group can deprotonate the
neighboring outer-sphere water and produce an external
hydroxide, which then attacks the phosphodiester linkage of
the adjacent substrate. The present switching mechanism (i.e.,
the formation and cleavage of NH···O hydrogen bond) is
possible in some proteins. Figure S2b in the Supporting
Information shows an endonuclease active site found in an
Figure 11. Contributions of the intramolecular NH···O hydrogen
bonds to Mg−O bonds.
coordinated oxygen atom elongates the Mg−O bond while a
hydrogen bond to the carbonyl group shortens the Mg−O
bond. Doubly NH···O hydrogen-bonded carboxylate is a Lewis
base that is too soft or weak; therefore, it cannot coordinate to
the Mg ion in a trans configuration; however, it was successful
in cis-dicarboxylate coordination. The significantly weak Mg−O
(carboxylate) bond strengthens the Mg−O (water) bond,
similar to the trans influence caused by a competitive charge-
transfer or delocalization of electrons. The experimental and
theoretical results led to the proposed switching mechanism for
controlling the acidity of the coordinated water and basicity of
the deprotonated Mg−OH moiety. Our switching mechanism
presents a possible solution to the problem of incompatible
properties such as a strong acid with a strong conjugate base of
the coordinated water required for catalytic activity in
hydrolysis.
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(24) Okamura, T.; Ushijima, Y.; Omi, Y.; Onitsuka, K. Inorg. Chem.
2013, 52, 381−394.
ASSOCIATED CONTENT
* Supporting Information
■
S
(25) Okamura, T.; Kunisue, K.; Omi, Y.; Onitsuka, K. Dalton Trans.
2013, 42, 7569−7578.
X-ray crystallographic data for models 1−8, and 2,6-
(CH3CONH)2C6H3COOH in CIF format, details for the
ligand (Table S1, Figure S1), geometrical parameters of models
3−6 (Tables S2−S5), results of DFT calculations (Tables S6,
S7), schematic drawing of the active sites (Figure S2). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(26) Okamura, T.; Taniuchi, K.; Lee, K.; Yamamoto, H.; Ueyama, N.;
Nakamura, A. Inorg. Chem. 2006, 45, 9374−9380.
(27) Onoda, A.; Yamada, Y.; Nakayama, Y.; Takahashi, K.; Adachi,
H.; Okamura, T.; Nakamura, A.; Yamamoto, H.; Ueyama, N.;
Vyprachticky, D.; Okamoto, Y. Inorg. Chem. 2004, 43, 4447−4455.
(28) Onoda, A.; Yamada, Y.; Okamura, T.; Yamamoto, H.; Ueyama,
N. Inorg. Chem. 2002, 41, 6038−6047.
(29) Drake, S. R.; Sanderson, K. D.; Hursthouse, M. B.; Malik, K. M.
A. Inorg. Chem. 1993, 1993, 1041−1044.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tokamura@chem.sci.osaka-u.ac.jp.
Notes
■
(30) Yamada, Y.; Ueyama, N.; Okamura, T.; Mori, W.; Nakamura, A.
Inorg. Chim. Acta 1998, 275−276, 43−51.
(31) Onoda, A.; Yamada, Y.; Takeda, J.; Nakayama, Y.; Okamura, T.;
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The authors declare no competing financial interest.
(32) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, M.;
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ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI (Grant No.
23655049).
■
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