Synthesis and structures of soluble magnesium and zinc carboxylates containing intramolecular NH?O hydrogen bonds in nonpolar solvents

Article abstract of DOI:10.1039/c5dt00053j

Readily soluble magnesium and zinc carboxylates [M(Ln)₂(H₂O)₄] (MLn₂) (M = Mg, Zn; L1 = O₂C-2-Ar₃CCONH-6-n-BuCONHC₆H₃; L2 = O₂C-2-Ar₃CCONHC₆H₄; Ar = 4-t-BuC₆H₄) containing intramolecular NH?O hydrogen bonds in nonpolar solvents were synthesized and their molecular structures were determined by X-ray analysis. The complexes were crystallized in the trans or cis configuration. The M-O bond distances were dependent on the mode of the hydrogen bonds. ¹H NMR spectral measurements revealed a fast trans-cis isomerization of MLn₂ in CDCl₃, which was converted into a unique fac-[M(Ln)₃(H₂O)₃]^- (fac-[MLn₃]^-) by the addition of equimolar [Ln]^-. The theoretical calculations supported the existence of the facial configuration. The coordinated water molecules of MLn₂ were detected by ¹H NMR spectroscopy and the acidity was estimated in the order of ML1₂ > ML2₂. Calcium afforded only the dinuclear complex, [Ca₂(L1)₂(H₂O)₅(1,4-dioxane)] (Ca₂L1₄), which showed a low hydrolytic activity.

Full text of DOI:10.1039/c5dt00053j

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ARTICLE
Synthesis and structures of soluble magnesium and
zinc carboxylates containing intramolecular NH•••O
hydrogen bonds in nonpolar solvents†
Cite this: DOI: 10.1039/x0xx00000x
Taka-aki Okamura,* Ryosuke Furuya and Kiyotaka Onitsuka
Received 00th January 2012,
Accepted 00th January 2012
Readily soluble magnesium and zinc carboxylates [M(Ln)2(H2O)4] (MLn2) (M = Mg, Zn; L1
=
DOI: 10.1039/x0xx00000x
O2C-2-Ar3CCONH-6-n-BuCONHC6H3; L2 = O2C-2-Ar3CCONHC6H4; Ar = 4-t-BuC6H4)
containing intramolecular NH···O hydrogen bonds in nonpolar solvents were synthesized and
their molecular structures were determined by X-ray analysis. The complexes were crystallized
in the trans or cis configuration. The M–O bond distances were dependent on the mode of the
hydrogen bonds. 1H NMR spectral measurements revealed a fast trans-cis isomerization of
MLn2 in CDCl3, which was converted into a unique fac-[M(Ln)3(H2O)3]− (fac-[MLn3]−) by
the addition of equimolar [Ln]−. The theoretical calculations supported the existence of the
facial configuration. The coordinated water molecules of MLn2 were detected by 1H NMR
www.rsc.org/
spectroscopy and the acidity was estimated in the order of ML12
>
ML22. Calcium afforded
only dinuclear complex, [Ca2(L1)2(H2O)5(1,4-dioxane)]
(Ca2L14), which showed low
hydrolytic activity.
to bind the third carboxylate in a chelate fashion.21,22 Moreover,
a hydrated Mg2+ ion can thermodynamically accept up to the
third carboxylate in a medium with a low dielectric constant (
≤ 4).12
Introduction
Naturally abundant magnesium is essential in biological
processes involving phosphorylated compounds, such as repair,
duplication, expression, and storage of genetic information, and
energy metabolism processes.1-4 These are closely associated
with the life cycle of viruses and serious diseases.5-7
Magnesium-dependent phosphatase is a prevalent enzyme that
requires Mg2+ ions or analogous divalent metal ions (normally
Mn2+) in order to function.2 The active sites are usually
octahedral six-coordinated complexes containing labile Mg–O
(carboxylate) bonds, which are supported by high intracellular a
concentration of Mg2+ ions in vivo.8,9
Recently, we reported the significant contributions of
intramolecular NH···O hydrogen bonds to Mg–O bonds in
magnesium carboxylate complexes, as evidenced by X-ray
analysis and theoretical calculations. The direct hydrogen bond
to the coordinated oxygen atom of the carboxy group elongates
the Mg–O (carboxylate) bond and shortens the Mg–OH2 bonds,
while the hydrogen bond to the uncoordinated carboxy oxygen
atom shortens the Mg–O (carboxylate) bond. The opposite
effect was also seen, depending on the mode of the hydrogen
bond, which led to the proposal of a new switching mechanism
based on controlling the acidity of the coordinated water
molecule by regulating the strength of the Mg–OH2 bond.23
However, the insolubility of the complexes prevented an
investigation of the real solution structures and experimental
evaluation of the hydrolytic activity.
In spite of the importance of the chemistry of magnesium
carboxylates, reports regarding their solution structures are very
limited.10 Theoretical approaches using crystal structures of
enzymes or synthetic models have given us some insights into
their solution structures and the mechanisms of their hydrolytic
reactions involving inner-sphere/outer-sphere pathways.11

17
Many magnesium carboxylates have been reported and
structurally characterized.15,18 However, most of these are
sparingly soluble in nonpolar solvents and dissociate to
solvated ion pairs in a polar solution.19,20 At the metal-binding
site of ribonucleases, three carboxylates are conserved. Two of
the three carboxylates are bound moderately to a metal ion.
Theoretical predictions have indicated that the Mg2+ ion
interacts with the third carboxylate in the outer shell of the
protein matrix while the biologically inactive Ca2+ ion prefers
In a study on molybdenum enzyme models, we found that
the very bulky and hydrophobic Ar3CCONH (Ar = 4-t-BuC6H4)
group
sufficiently
covered
the
ionic
core
of
monooxomolybdenum dithiolate, and surprisingly, improved
the solubility in nonpolar solvents.24,25 Such low-dielectric
media simulate the buried metal-binding cavity in the native
protein matrix.26 This finding encouraged us to apply these
groups to magnesium carboxylates with ionic bonds.
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In this Article, we present the synthesis of readily soluble 2,6-(CH3CONH)2C6H3COOH (1.02 g, 4.3 mmol) was
carboxylic acids with the Ar3CCONH groups, 2,6- suspended in a 10% HCl aqueous solution (144 mL). After
(Ar3CCONH)2C6H3COOH
BuCONHC6H3COOH (L1H), and 2-Ar3CCONHC6H4COOH yellow solution. The resulting aqueous solution of 2,6-
L2H). Sterically hindered L0H was designed to prevent the (NH2)2C6H3COOH·2HCl was basified with NaHCO3, washed
(
L0
H
),
2-Ar3CCONH-6-n- stirring for 30 min at 90 °C, the suspension changed to a pale
(
second coordination of the ligand to give [Mg(L0)(H2O)5]+, with Et2O, and dried under reduced pressure. The residue was
with water coordinated trans to the carboxylate ligand, which suspended in CH2Cl2 (20 mL). Upon the addition of
is analogous to the crystal structure of [Mg(O2C-2- triethylamine (3.5 mL, 25 mmol) cooling in an ice bath, the
CH3CONHC6H4)(H2O)5]+.23 However, this trial met with mixture turned yellow. A solution of Ar3CCOCl (2.02 g, 4.4
failure. The desired magnesium complexes with L1 or L2 were mmol) in CH2Cl2 (15 mL) was added carefully to the mixture
readily soluble in nonpolar solvents. The corresponding zinc cooling in an ice bath. After stirring overnight at 0 °C, the
complexes with a stronger Zn–O bond26 were synthesized for mixture was concentrated to dryness under reduced pressure.
comparison. The analogous complexes of the biologically Toluene was added to the residue and was washed with 2% HCl
inactive Ca2+ ion were also prepared. The molecular structures aq. and sat. NaCl aq., successively. The solution was dried over
of MLn2 in the crystal and the hydrolytic reactions have MgSO4 and evaporated to dryness under reduced pressure. The
already been communicated.27
A detailed description is residue was recrystallized from ethanol to give colorless
presented here with additional data; moreover, the behavior of crystals, which were removed by filtration, and the filtrate was
the complexes in solution and the formation of novel anionic evaporated. The residue (1.45 g, 2.5 mmol) and NEt3 (1.8 mL,
tris(carboxylate) complexes are discussed. Hydrolysis of 12 mmol) were dissolved in CH2Cl2 (20 mL) cooling in
phosphoric ester by the metal carboxylates is also mentioned.
dryice/methanol bath and then valeryl chloride (0.26 mL, 2.2
mmol) in CH2Cl2 (20 mL) was added dropwise to the solution.
The resulting yellow solution was stirred cooling in
dryice/methanol bath for 6.5 h and at 2 °C for 19 h. The
solution was concentrated to dryness under reduced pressure.
Toluene was added to the residue and washed with 2% HCl aq.
and sat. NaCl aq., successively. The solution was dried over
Na2SO4 and evaporated. The residue was recrystallized from
ethanol to give colorless crystalline solid and yellow solution.
Yellow solution was separated and concentrated under reduced
pressure. Addition of n-hexane to the residue gave colorless
Experimental
All solvents were dried and distilled before use and
amidation was carried out under argon atmosphere using
Schlenk technique. Ar3CCOCl (Ar- = t-BuC6H4-) and 2,6-
(CH3CONH)2C6H3COOH were prepared by the literature
procedure.25,28
2,6-(Ar3CCONH)2C6H3COOH (L0H)
1
crystalline solid. Yield: 469 mg (16%). H NMR (500 MHz,
2,6-(CH3CONH)2C6H3COOH (0.170 g, 0.72 mmol) was
suspended in a 10% HCl aqueous solution (20 mL). After
stirring for 30 min at 90 °C, the suspension changed to a pale
yellow solution. The aqueous solution which contains 2,6-
(NH2)2C6H3COOH·2HCl was basified with NaHCO3, and the
solution was washed with Et2O and dried under reduced
pressure. To the suspension of the residue in CH2Cl2 (30 mL)
was added triethylamine (0.50 mL, 3.6 mmol), the mixture was
cooled in an ice bath, and the color of the mixture turned
yellow. The solution of Ar3CCOCl (0.683 g, 1.4 mmol) in
CH2Cl2 (10 mL) was added carefully to the mixture cooling in
an ice bath. After stirring overnight at 0 °C, the mixture was
dried under reduced pressure, and the residue was extracted
with dichloromethane. The organic layer was washed with 2%
HCl aq, water, 4% NaHCO3 aq, water, and sat. NaCl aq.,
successively. The organic layer was dried over Na2SO4 and
evaporated to dryness. The residue was recrystallized from
ethyl acetate to give colorless crystals. Yield: 0.452 g (61%).
CDCl3): 9.94(s, 1H, NH), 9.38(s, 1H, NH), 8.23 (m, 2H, Ar),
7.49 (d, 1H, Ar), 7.30 (d, 6H, Ar), 7.19 (d, 6H, Ar), 1.30 (s,
27H, t-Bu), 2.33 (t, 2H, n-Bu), 1.66 (m, 2H, n-Bu), 1.35 (m,
2H, n-Bu), 0.91 (t, 3H, n-Bu). Anal. Calcd for C44H54N2O4: C,
78.30; H, 8.06; N, 4.15. Found: C, 78.17; H, 8.00; N, 4.25.
2-Ar3CCONHC6H4COOH (L2H)
To a solution of 2-aminobenzoic acid (279 mg, 2.0 mmol) and
triethylamine (0.84 mL, 6.0 mmol) in CH2Cl2 (10 mL) was
added a solution of Ar3CCOCl (956 mg, 2.0 mmol) in CH2Cl2
(10 mL) at 0 °C. After stirring overnight at room temperature,
the solution was concentrated under reduced pressure. The
residue was mixed with ethyl acetate, washed with 2% HCl aq.
and sat. NaCl aq., successively, and dried over Na2SO4. After
removal of solvents under reduced pressure, the residual
powder was recrystallized from CH2Cl2/n-hexane to afford
1
colorless needles. Yield: 229 g (19.7%). H NMR (500 MHz,
CDCl3): 10.64 (s, 1H ,NH), 8.91(dd, 1H, Ar), 8.00 (dd, 1H,
Ar), 7.58 (m, 1H, Ar), 7.28 (d, 6H, Ar), 7.20 (d, 6H, Ar), 7.08
(m, 1H, Ar), 1.28 (s, 27H, t-Bu). Anal. Calcd for C39H45NO3: C,
81.32; H, 7.88; N, 2.43. Found: C, 81.12; H, 7.79; N, 2.43.
1H NMR (500 MHz, CDCl3):
δ7.32 (d, 12H, Ar), 7.25 (d, 12H,
Ar), 1.31 (s, 27H, t-Bu). Anal. Calcd for C75H92N2O6 ((2,6-
Ar3CCONH)2C6H3COOH)·AcOEt): C, 80.61; H, 8.31; N, 2.51.
Found: C, 80.41; H, 8.21; N, 2.60.
(NMe4)[O2C-2-Ar3CCONH-6-n-BuCONHC6H3] ((NMe4)[L1])
2-Ar3CCONH-6-n-BuCONHC6H3COOH (L1H)
To a solution of L1H (107 mg, 0.16 mmol) in EtOH (30 mL)
was added an aqueous solution of tetramethylammonium
2 | J. Name., 2012, 00, 1-3
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acetate (55 mM, 3.0 mL, 0.17 mmol) and the solution was 8.05; N, 1.83. Found: C, 70.76; H, 7.93.; N, 1.84. [Mg(O2C-2-
evaporated . The residue was dissolved in EtOH and evaporated. Ar3CCONHC6H4)2(EtOH)4] (MgL22(EtOH)) was also obtained
This manipulation was repeated several times to remove acetic by the recrystallization from EtOH as colorless blocks. The
acid completely. The residue was recrystallized from 1,4- easy release of the EtOH molecules was also observed as
dioxane/n-hexane to afford colorless needles. Yield: 111 mg mentioned for MgL12(EtOH).
(93%). 1H NMR (500 MHz, CDCl3): 13.05(s, 1H, NH),
[Zn(O2C-2-Ar3CCONH-6-n-BuCONHC6H3)2(H2O)4] (ZnL12)
12.97(s, 1H, NH), 8.25 (m, 2H, Ar), 7.49 (d, 1H, Ar), 7.25 (s,
+
12H, Ar), 2.89 (s, 12H, NMe4 ), 1.28 (s, 27H, t-Bu) , 2.33 (t, This compound was synthesized by the same method described
2H, n-Bu) , 1.66 (m, 2H, n-Bu) , 1.35 (m, 2H, n-Bu) , 0.91 (t, for MgL12 except for using L1H (71.5 mg, 0.11 mmol) and
3H, n-Bu). Anal. Calcd for C52H73N3O6 ((NMe4)[L1]·(1,4- Zn(OAc)2 (14.8 mM, 3.70 mL, 0.055 mmol). Recrystallization
dioxane)): C, 74.69; H, 8.80; N, 5.03. Found: C, 74.94; H, 8.31; from 1,4-dioxane/water afforded colorless needles. Yield: 52.7
N, 5.37. The presence of 1,4-dioxane was confirmed mg
(65%).
Anal.
Calcd
for
C96.8H131N4O16.3Zn
quantitatively by 1H NMR spectra (at ~3.7 ppm).
([Zn(L1)2(H2O)4]
·2.2(1,4-dioxane) – 0.1(H2O)): C, 69.32; H,
7.90; N, 3.34. Found: C, 69.55; H, 7.68; N, 3.49.
(NMe4)[O2C-2-Ar3CCONHC6H4] ((NMe4)[L2])
[Zn(O2C-2-Ar3CCONHC6H4)2(H2O)4] (ZnL22)
This compound was synthesized in the same manner described
for (NMe4)[L1]] using L2H (189 mg, 0.33 mmol) and This compound was synthesized by the same method described
tetramethylammonium acetate (43.7 mg, 0.33 mmol) to afford for MgL22 except for using L2H (226 mg, 0.39 mmol) and
1
colorless needles. Yield: 176 mg (82%). H NMR (500 MHz, Zn(OAc)2 (35.1 mg, 0.19 mmol). Colorless needles were
CDCl3):
δ
13.37 (s, 1H ,NH), 8.73(dd, 1H, Ar), 8.06 (dd, 1H, obtained. Yield: 43.0 mg (17%). Anal. Calcd for
1/2(1,4-dioxane)·(H2O)): C,
(s, 12H, NMe4 ), 1.28 (s, 27H, t-Bu). Anal. Calcd for 71.34; H, 7.69; N, 2.03. Found: C, 71.05; H, 7.38.; N, 2.08.
Ar), 7.31(m, 1H, Ar), 7.28(d, 12H, Ar), 7.23 (s, 12H, Ar), 3.12 C82H105N2O12.3Zn ([Zn(L2)2(H2O)4]
·
+
C49H68N2O6 ((NMe4)[L2]·1.5(1,4-dioxane)): C, 75.35; H, 8.78;
N, 3.59. Found: C, 75.29; H, 8.30; N, 4.40. The presence of
1,4-dioxane was confirmed by 1H NMR spectra.
[Ca2(O2C-2-Ar3CCONH-6-n-BuCONHC6H3)4(H2O)5(1,4-
dioxane)] (Ca2L14)
To a solution of L1H (55.1 mg, 0.082 mmol) in ethanol (30
mL) was added an aqueous solution of Ca(OAc)2·H2O (62.3
[Mg(O2C-2-Ar3CCONH-6-n-BuCONHC6H3)2(H2O)4] (MgL12)
The metal complexes described in this paper were synthesized mM, 0.6 mL, 0.037 mmol) at room temperature and the
by a similar procedure to the literature.23 To a solution of L1
solution was dried under reduced pressure. The residue was
(56.6 mg, 0.084 mmol) in ethanol (30 mL) was added an treated in the same procedure described for MgL12
aqueous solution of Mg(OAc)2 4H2O (136 mM, 0.32 mL, 0.044 Recrystallization from 1,4-dioxane/water afforded colorless
H
.
·
mmol) at room temperature and the solution was dried in vacuo. blocks. Yield: 32.3 mg (59%). Anal. Calcd for
The residue was dissolved in ethanol, and the solution was C180H230Ca2N8O23 ([Ca2(L1)4(H2O)5(1,4-dioxane)]): C, 73.19;
evaporated under reduced pressure. This process was repeated H, 7.85; N, 3.79. Found: C, 73.24; H, 8.01; N, 3.82.
several times to remove acetic acid completely. The residue
Physical measurements
was recrystallized from 1,4-dioxane/water to afford colorless
blocks. Yield: 22.1 mg (36%). Anal. Calcd for 1H nuclear magnetic spectroscopy (1H NMR) spectra were
C97.2H138MgN4O19.3
dioxane) 2.7(H2O)): C, 68.57; H, 8.21; N, 3.28. Found: C, using CDCl3 or CD2Cl2 solution at 30 °C or variable
68.57; H, 8.12; N, 3.30. When the product was recrystallized temperatures (30, 0, −30, −60, and −90 °C). 31P NMR spectra
from EtOH/n-hexane, [Mg(O2C-2-Ar3CCONH-6-n- were obtained on a JEOL ECA-500 spectrometer in CDCl3 at
([Mg(L1)2(H2O)4]·2.3(1,4- obtained on a JEOL ECS-400 and ECA-500 spectrometers
·
BuCONHC6H3)2(EtOH)4] (MgL12(EtOH)) was obtained as 30 °C, where 85% H3PO4 was used as the external standard. 13
C
colorless columns. The coordinated EtOH molecules were NMR, 1H-1H correlation spectroscopy (COSY), nuclear
easily removed under reduced pressure and replaced by H2O in Overhauser effect (NOE) correlated spectroscopy (NOESY),
air.
1H-13C hetero-nuclear single quantum coherence (HSQC),
hetero-nuclear multiple bond connectivity (HMBC) spectra of
L1H and L2H were obtained on a Bruker AVANCE700
[Mg(O2C-2-Ar3CCONHC6H4)2(H2O)4] (MgL22)
L2H (371 mg, 0.64 mmol) and Mg(OAc)2·4H2O (75.6 mg, 0.35 spectrometer in CDCl3 at 30 °C.
mg) were dissolved in a mixture of ethanol and water at room
temperature and the solution was dried in vacuo. The residue
X-ray structure determination
was dissolved in ethanol, and the solution was concentrated to Each single crystal of L0H∙3(AcOEt), (NMe4)[L1]∙2(H2O)∙1,4-
dryness under reduced pressure. This process was repeated dioxane,
several times as mentioned above. The residue was dioxane)∙4(H2O),
L2H∙1/2(1,4-dioxane),
Ca2L14·4(1,4-
and
MgL12(EtOH)·4(EtOH),
recrystallized from 1,4-dioxane/water to give colorless needles. MgL22(EtOH)·5(EtOH) was selected carefully and mounted on
Yield: 458 g (76%). Anal. Calcd for C88.4H119MgN2O16.3 MicroMount™ 200 with Nujol, which was frozen
([Mg(L2)2(H2O)4]·2.6(1,4-dioxane)·1.1(H2O)): C, 70.73; H, immediately in a stream of cold nitrogen at 200 K. Data
μ
m
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collection was made on a Rigaku RAPID II Imaging Plate area protonated and then hydrolyzed by traces of water in the
detector with Mo-K radiation (0.71075 Å) using MicroMax- solvents. The reaction was dependent on the polarity of the
α
007HF microfocus rotating anode X-ray generator and solvents. Hydrolysis did not occur in dimethyl sulfoxide which
VariMax-Mo optics. The structure was solved by direct weakens the hydrogen bond. The hydrolyzed product, 2-t-
methods29,30 and expanded Fourier techniques using SHELXL- BuCONH-6-NH2C6H3COOH, and singly hydrogen-bonded 2-t-
2014/6.30 Non-hydrogen atoms were refined anisotropically. BuCONHC6H4COOH were stable in chloroform; therefore, a
Some H atoms of amide groups were found in the differential strong ―double‖ hydrogen bond is essential in nonpolar solvents.
Fourier map, then located there, and their coordinates were L2
H
was
prepared
by
a
general
procedure.
refined. The other H atoms were generated by the riding and Tetramethylammonium salts of L1H and L2H, (NMe4)[L1] and
rotating model in SHELXL-97.30
(NMe4)[L2], were prepared by the reaction with the
corresponding acetate, followed by exhaustive removal of the
resulting acetic acid under reduced pressure, as described in the
Kinetic analysis for hydrolysis of TNPP
A solution of TNPP (5 mM) and MLn2 (or Ca2L14, 2.5 mM) in literature.32 These compounds were fully characterized by X-
CD2Cl2 was heated at 50 °C in a sealed NMR tube and the ray analysis, 1H NMR spectroscopy, and elemental analysis.
1
progress of reaction was monitored by the H NMR signals of
4-nitrophenol.
Density Functional Theory (DFT) Calculations
Geometry optimizations were performed using Becke’s three
parameter hybrid functionals (B3LYP) in Gaussian 0931
program package using 6-31G(d,p) basis set. Initial models,
−
mer-[MgL13
]
and fac-[MgL23]−, were constructed by the
modifications of the X-ray structures, MgL12, MgL12(EtOH),
and MgL22. The structures were roughly optimized using 3-
21G* basis set. Introduction of t-BuCONH groups to fac-
−
[
MgL23
]
gave initial model of fac-[MgL13]−, which was
roughly optimized at 3-21G* level. The optimized structures of
−
mer-[MgL13
]
and fac-[MgL13]− were re-optimized by using
the higher level basis set described above.
Results and discussion
Synthesis of the ligands
A ligand with two bulky Ar3CCONH- (Ar = 4-t-BuC6H4)
groups, L0H, was synthesized by acylation of 2,6-
diaminobenzoic acid, which was freshly prepared from 2,6-
di(acetylamino)benzoic acid, as described in the literature23
(Scheme 1). Low temperature is necessary to prevent
decarboxylation of the product. The reaction at 50 °C gave 1,3-
Scheme 1 (i) 2Ar3CCOCl/NEt3, CH2Cl2, 0
°C. (ii) Ar3CCOCl/NEt3, CH2Cl2, 0 °C. (iii) n-
BuCOCl/NEt3, CH2Cl2, -78 C then 0 °C. (iv) M(OAc)2/EtOH (M = Mg, Zn, Ca) then
°
recryst. from 1,4-dioxane/water.
(Ar3CCONH)2C6H4 as
a
byproduct. Unsymmetrically
For L0H, (NMe4)[L1], and L2H, suitable crystals for X-ray
analysis were obtained. The crystallographic parameters and
molecular structures are shown in Table S1 and Fig. S1.† The
L0H molecule was crystallized as a monomeric structure to
avoid steric congestion of the bulky substituents. The OH group
weakly interacted with ethyl acetate as the crystallization
solvent. On the other hand, L2H was found as a dimeric
structure in the crystal. Such dimerization is quite common and
well-known for general carboxylic acids in the solid state or in
nonpolar solvents. The tetramethylammonium cation of
(NMe4)[L1] is present close to the carboxy group and water of
crystallization, demonstrating the presence of intermolecular
CH···O hydrogen bonds. In any case, the amide NH group is
oriented towards the carboxy group, which strongly suggests
the presence of an intramolecular NH···O hydrogen bond.
substituted ligand, L1H, was synthesized by stepwise acylation.
The addition of one equivalent of Ar3CCOCl afforded the
desired 2-Ar3CCONH-6-NH2C6H3COOH and the undesired
disubstituted L0H, which was separated out as crystals by
careful recrystallization from ethanol and subsequently
removed by filtration. The intermediate product was purified
with up to ~ 90% purity by repeating the recrystallization
procedure mentioned above. The second acylation yielded L1H.
L1H is stable in the solid state but gradually decomposed in
chloroform or acidic solution at ambient temperature to give a
selectively
hydrolyzed
product,
2-Ar3CCONH-6-
NH2C6H3COOH. Such hydrolysis was also observed for 2,6-(t-
BuCONH)2C6H3COOH in chloroform. The doubly NH···O
hydrogen-bonded carboxylic acid is very acidic32 and thus the
oxygen atom of the amide group was intra- or intermolecularly
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The 1H NMR spectra of LnH (
= 1, 2) in CDCl3 are shown in Fig. S2.† The signals were fully
n = 0–2) and (NMe4)[Ln] (n
assigned by their correlations using two-dimensional NMR
techniques. The downfield shifted signals of NH for
(NMe4)[L1] (at 13.04 and 12.64 ppm) and for (NMe4)[L2] (at
13.37 ppm) suggest the presence of strong NH···O hydrogen
bonds, as reported previously.32 The NH signal of L2H at 10.55
ppm, further downfield than that of L0H at 9.51 ppm, also
suggests the presence of a stronger hydrogen bond, which was
probably caused by the dimeric structure of L2H in CDCl3,
similar to that in the crystal mentioned above. The
intermolecular OH···O hydrogen bonds increase the electron
density on the oxygen atom or the basicity, resulting in a
stronger hydrogen bond.
Synthesis of magnesium, zinc, and calcium complexes
The metal carboxylate complexes were synthesized by a ligand-
exchange reaction between metal acetate and the corresponding
carboxylic acid, followed by exhaustive removal of free acetic
acid (Scheme 1), as reported previously.23 Recrystallization
from a hydrous solvent, 1,4-dioxane/water, gave the desired
mononuclear complexes [M(Ln)2(H2O)4] (MLn2) (M = Mg,
Zn;
crystalline dimeric structure [Ca2(L1)4(H2O)5(1,4-dioxane)]
Ca2L14) (Chart 1). The reaction between Ca(OAc)2 and L2
gave a gel-like product with poor solubility, which could not be
characterized. When MgLn2 ) was recrystallized from
ethanol under anhydrous conditions, [M(Ln)2(EtOH)4]
MLn2(EtOH)) was obtained as crystals. The coordinated
n = 1, 2). However, the calcium complex was isolated as a
(
H
(n = 1,2
(
ethanol molecules were easily removed under reduced pressure
and were replaced by water molecules in air.
Chart 1 Metal complexes containing NH···O hydrogen bonds.
In the case of L0H, similar trials were unsuccessful;
therefore, the starting material was changed to the more basic
Mg(OCH3)2. The 1H NMR spectra indicated some perturbations
in the presence of metal ions. The aromatic proton signals of
the C6H3 moiety were shifted upfield and became slightly
narrower, while the NH signal was clearly sharpened. These
results suggest that some interactions are occurring but that
direct coordination is probably absent. Therefore, the most
plausible structure is [Mg(H2O)6][L0]2. Such an ion pair of a
hydrated magnesium cation and anionic ligands was reported
previously.23 The reaction between Ca(OH)2 and L0H gave
similar results and recrystallization of the crude product gave
crystals of starting L0H.
Molecular structures of metal carboxylates
The molecular structures of MLn2 (M = Mg, Zn; n = 1, 2) and
Ca2L14 were determined by X-ray analysis. The structures of
MLn2 have already been communicated previously;27 therefore,
the structural details are now described here. The
crystallographic data for Ca2L14 are listed in Table S1.† The
molecular structures are shown in Fig. 1 and 2. Each
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carboxylate ligand was coordinated to a metal ion in a stable
syn (Z) conformation.33 MgL12
MgL22, and ZnL22 were
,
crystallized in the typical trans configuration found in many
magnesium dicarboxylates;18,23,34,35 however, ZnL12 was
crystallized in the cis configuration. In the previous paper, we
described the formation of magnesium carboxylates containing
intramolecular NH···O hydrogen bonds and concluded that a
doubly NH···O hydrogen-bonded carboxylate is too weak or
soft Lewis base to coordinate directly to the magnesium ion in
the trans configuration and only the cis-dicarboxylate was
isolated.23 Based on this logic, cis-ZnL12 is the normal
structure and trans-MgL12 is thus a surprising result. We
describe here the reason why trans-MgL12 could be isolated,
despite the failure of many trials in the previous paper. The
previous complexes were sparingly soluble in nonpolar solvents
but dissolved in polar solvents. Polar solvents stabilized
hydrated or solvated magnesium ions. Such solvated soft
cations should weakly interact with doubly hydrogen-bonded
carboxylate anions. The coordinated solvent was hardly
removed during recrystallization. The present complex is
soluble in nonpolar solvents, which indicates that the Mg2+–L1−
ion pair is stabilized in nonpolar solvents and the attack of a
water molecule on the magnesium ion must be very limited by
the hydrophobic surroundings. In the crystal of MgL12, one
water molecule is present near the coordinated water to form
OH···O hydrogen bonds (Fig. S3†). The water molecule is
buried with a perfect fit in the hydrophobic pocket formed from
the Ar3C and n-Bu groups (Fig. S4†). The open front side in Fig.
S4a† is covered by 1,4-dioxane in the crystal. The surroundings
are probably retained in the recrystallization solvent, i.e., a
mixture of 1,4-dioxane/water, resulting in a stable trans-
dicarboxylate configuration in the crystal. Analogous
complexes with the coordination of ethanol instead of water,
[Mg(O2C-2-Ar3CCONH-6-n-BuCONHC6H3)2(EtOH)4]
(
(
MgL12(EtOH)) and [Mg(O2C-2-Ar3CCONHC6H4)2(EtOH)4]
MgL22(EtOH)), were crystallized as cis-MgL12(EtOH) and
trans-MgL22(EtOH) structures (Fig. 3). These results suggest
that the selection of trans or cis is unclear and depends on the
packing in the crystal. As described below, a fast trans-cis
isomerization should occur in solution.
Fig. 1 Molecular structures of (a) trans-MgL12, (b) cis-ZnL12, and (c) Ca2L14
.
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Fig. 3 Molecular structures of (a) MgL12(EtOH) and (b) MgL22(EtOH).
Calcium carboxylates generally prefer bridging or
polymeric structures. We previously reported a neutral dimeric
calcium complex using a chelate ligand with intramolecular
NH···O hydrogen bonds.36 Because the reaction of Ca(OAc)2
with L2H gave a sparingly soluble gel-like complex, the
product most likely has polymeric structure. The sufficient
bulkiness of L1 prevented the formation of the polymeric
structure to afford dimeric Ca2L14 (Chart1, Fig. 1c). The
molecule was crystallized in a centrosymmetric space group
and a crystallographic inversion center is present at the center
of the dinuclear structure. Two calcium atoms were found in
close proximity crystallographically; therefore, the structure
was solved as an unsymmetrical dimer, assuming that two
equivalent disordered parts are present with a half occupancy.
The molecule did not contain any bridging carboxylate unit and
each calcium site had monomeric, seven-coordinate geometry
comprised of chelate and monodentate carboxylates, an amide
carbonyl, and three solvent molecules (three water or one 1,4-
dioxane and two water molecules). Two Ca–O distances in the
chelate carboxylate ligand are significantly different each other
like a monodentate ligand. Although the structure was highly
disordered and R factors were large, the coordination modes of
Fig. 2 Molecular structures of (a) MgL22 and (b) ZnL22
.
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the carboxylate ligands were found different from the reported The complexes, MLn2 and Ca2L14, were readily soluble in
2-coordination of the analogous carboxylate ligands with nonpolar solvents, such as chloroform, dichloromethane, and
1
NH···O hydrogen bonds.36,38 Because the coordination number toluene. The H NMR spectra of these complexes in CDCl3 are
and geometry were very different from the other structures of shown in Fig. 4 and 5 along with the spectra of L1H and L2H.
MLn2, the structural comparisons are limited in a series of Very broad signals were observed for all the metal carboxylates
MLn2
.
although the original LnH showed sharp signals. As described
above, MgL12 and ZnL12 were crystallized with trans and cis
Selected bond distances of MLn2
(
M = Mg, Zn; n = 1, 2)
are listed in Table 1. Intra- and intermolecular hydrogen bonds geometry, respectively; therefore, the similarity between the
are shown in Fig. S3.† The M–O (carboxylate) distances are spectra of these complexes suggests fast trans-cis
a
dependent on the mode of the NH···O hydrogen bond as isomerization on the NMR time scale (Fig. 4a, b). These spectra
reported previously.23,27 The hydrogen bond to the revealed the real averaged solution structure in nonpolar
1
uncoordinated oxygen atom of the carboxylate shortens the M– solvents. H NMR spectra of ZnL12 in CD2Cl2 were measured
O bond in ML22, while a double NH···O hydrogen bond at lower temperatures to depress the isomerization; however,
elongates the M–O (carboxylate) bond in ML12. The M–OH2 broad peaks were not separated and sharpened (Fig. S5†). On
bonds are classified into two types; one forms an intramolecular the contrary, peaks became broad and complex at −90 °C,
OH···O=C hydrogen bond with the carboxylate ligand and the which suggests aggregation through intermolecular interactions.
other intermolecularly hydrogen bonds with crystalline solvents However, direct coordination of the amide carbonyl group to
or an amide carbonyl group. The latter M–OH2 bond clearly the metal ion hardly occurs because of the steric hindrance of
indicates the opposite tendency to the M–O (carboxylate) bond; the Ar3C group.
that is, the double NH···O hydrogen bond stabilized the short
M−OH2 bond. The mean M–OH2 distances were in the order of
ML12
< ML22. Similar trends were found for Mg–O
(carboxylate) distances of cis-MgL12(EtOH) and trans-
MgL22(EtOH) although the dependency of Mg–O (ethanol)
was not so clear (Table S2†).
Table1 Selected bond distances (Å) for MLn2 (M = Mg, Zn; n = 1,2)
MgL12
2.053(2)
2.058(2)
2.083(2)a
2.070
MgL22
2.037(3)
2.113(3)
2.095(3) a
2.104
ZnL12
2.069(2)
2.132(2)
2.101(2) a
2.117
ZnL22
2.040(3)
2.151(4)
2.100(5)a
2.126
M–O11
M–OH2
mean
C1–O11
C1–O12
1.266(3)
1.259(3)
1.261(4)
1.245(5)
1.270(3)
1.247(3)
1.281(7)
1.228(8)
aForming intramolecular OH···O=C hydrogen bond.
The small difference in the two C–O bond distances in
MgL12 indicates a delocalized structure for the carboxylate
anion. For example, (NMe4)[L1
] exhibits approximately
equivalent C–O bonds, 1.245(4) and 1.248(4) Å, while L2H has
single C1–O11 bond (1.316(3) Å) and double C1=O12
(1.223(3) Å) bond. A similar tendency was also found in L0H,
C1=O11 (1.245(7) Å) and C1–O12 (1.295(7) Å). Therefore, the
difference indicates an anionic character for the carboxylate
ligand in the complex. The anionic character is estimated in the
Fig. 4 1H NMR spectra of (a) MgL12, (b) ZnL12, (c) Ca2L14, and (d) L1H in CDCl3.
order of ML12
> ML22 and MgLn2 > ZnLn2. The oxygen atom
of the anionic carboxylate ligand increases the electron density
and should form a stronger NH···O hydrogen bond.
The effect of the hydrogen bonds is dependent on the
electron density of the oxygen atom. In the ionic Mg–O
(carboxylate) bond, electrons are localized on the oxygen atom
as compared with the zinc analogue. In the relatively covalent
Zn–O bond, electrons are delocalized between zinc and oxygen
atoms. The contribution of the hydrogen bond is probably
spread over the atoms, therefore, not so effective.
Solution structures of metal carboxylates in nonpolar solvents
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Preparation of mononuclear anionic magnesium and zinc
carboxylates
Previously,
tetrakis(carboxylate)
BuCONH)2C6H3}4], which showed sharp H NMR signals in
CDCl3.38 Herein, we attempt to prepare anionic complexes from
we
reported
complex,
an
anionic
calcium
(NEt4)2[Ca{O2C-2,6-(t-
1
MLn2. Fig. S6† shows the successive addition of (NMe4)[L1
]
into the solution of ZnL12 in CDCl3. The original signals of
ZnL12 were very broad, as described above. Upon addition of
equimolar (NMe4)[L1], the signals clearly became sharp and
distinct,
which
suggested
the
formation
of
(NMe4)[Zn(L1)3(H2O)3] ((NMe4)[ZnL13]). Another addition
did not cause any significant shifts but slightly broadened the
signals, indicating a fast (but slow in the NMR time scale)
ligand-exchange equilibrium between (NMe4)[ZnL13
] and
excess L1−. After further addition, the signals of excess
(NMe4)[L1] were observed. Because another signal was not
detected during the reaction, it can be concluded that
(NMe4)[Zn(L1)3] is the most stable structure under these
conditions. These results are consistent with the theoretical
prediction for water-substitution reactions of magnesium
carboxylates in a medium with a low dielectric constant.12 In a
Fig. 5 1H NMR spectra of (a) MgL22, (b) ZnL22, and (c) L2H in CDCl3.
similar manner, analogous complexes (NMe4)[MLn3] (
M
=
Mg
,
1
Zn; n = 1, 2) were prepared. The H NMR spectra of these
The chemical shifts of the signals for NH and the
coordinated water molecules are summarized in Table 2 along
with the data for the NH signals of LnH and (NMe4)[Ln]. The
downfield shift of the NH signal reflects the strength of the
NH···O hydrogen bond. The electron-rich oxygen atom of the
anionic carboxylate in (NMe4)[L2] ((NH), 13.37 ppm) formed
a strong NH···O hydrogen bond. The negative charge in
(NMe4)[L1] (13.04 and 12.94 ppm) was shared by two
hydrogen bonds, weakening each bond. Free carboxylic acid
L1H (9.99, 9.40 ppm) formed weak hydrogen bonds, while
dimeric L2H (10.55 ppm) has polarized carboxy groups, which
strengthen the hydrogen bond. The NH signals of MLn2 were
observed within the range of these values (10.5811.28 ppm) in
complexes in CDCl3 are shown in Fig. 6. All signals were
reasonably assigned. The downfield shifted signals of H2O
indicated that the coordinated water molecules remained. The
+
signals of NMe4 at relatively high field suggested a decreased
interionic interaction with a soft [MLn3]− anion, instead of a
hard carboxylate (Ln−) anion and/or a shielding effect by the
spatially neighboring aromatic rings in the hydrophobic media.
The signals of (NMe4)[Zn(L1)3] did not split at low
temperatures even at −90 °C (Fig. S7).† The signals, including
those of the solvents, were broader at −90 °C due to the
limitations of taking the measurements in CD2Cl2 (close to the
melting point). The presence of a single set of the ligands
suggests that the three ligands are equivalent; therefore, facial
coordination is the most plausible. Two isomers, fac- and mer-
the order of ML12
> ML22, which agreed with the estimated
[
ML3]−, are represented in Chart 2. Possible structures are very
order from the X-ray analysis.
limited by the substituent groups. To avoid steric congestion,
the very bulky Ar3C group should be external; that is, near to
the uncoordinated carbonyl group.
Table 2 1H NMR signals in CDCl3
MgL12
2.85
MgL22
2.61
ZnL12
2.86
ZnL22
2.35
Ca2L14
2.15
M–OH2
NH
11.28
10.72
11.09, 10.76
10.58
12.09,
11.52
L1H
9.99, 9.40
L2H
10.55
(NMe4)[L1] (NMe4)[L2]
13.04, 12.94 13.37
NH
The signals of the coordinated water molecules of MLn2
were observed in the range of 2.352.86 ppm, while residual
free water in CDCl3 is usually detected at ~ 1.5 ppm. Similar
spectra were obtained in toluene-d8. The coordinated water
molecules were more downfield-shifted than 2.1 ppm while
free water should be at ~ 0.4 ppm.37 The downfield shifts
indicate the acidity of the coordinated water in the order of
ML12
> ML22, which is consistent with the mean distance or
strength of the M–OH2 bonds in the crystal. The coordinated
water molecules of Ca2L14 were less acidic.
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The hydrolytic activities of the complexes were evaluated by
stoichiometric reactions with tris(4-nitrophenyl) phosphate
(TNPP) in dichloromethane, as communicated previously.27
A
solution of TNPP (5 mM) and each metal carboxylate ([M2+] =
5 mM) in dichlorometane-d2 afforded a hydrolyzed product, 4-
1
nitrophenol (NP), which was monitored by H NMR spectral
measurements. The yield of NP was plotted against time for
each complex (Fig. 7). Interestingly, naturally occurring
magnesium carboxylates were governed by the mode of the
NH···O hydrogen bond, while zinc carboxylates were not so
affected by the hydrogen bond. Moreover, the biologically
inactive calcium carboxylate showed low activity, although it
has a unique dimeric structure. The reaction rates were in the
order of ML22
M–O (carboxylate) bond. The order of the initial reaction rates
for the three metal ions was ZnL12 MgL12 CaL12, which
> ML12, which agreed with the strength of the
>
>
is in agreement with the acidity of the hydrated metal ions. The
reported pKa values of hydrated Zn2+, Mg2+, and Ca2+ ions are
9.0, 11.4, and 12.9, respectively.39 Anionic complex,
(NMe4)[MgL23], showed high hydrolytic activity caused by
basic free L2− anion generated by the dissociation of the ligand;
therefore, we could not evaluate the true activity of the anionic
complex.
Fig. 6 1H NMR spectra of (a) MgL12 + (NMe4)[L1] ((NMe4)[MgL13]), (b) ZnL12
+
(NMe4)[L1] ((NMe4)[ZnL13]), (c) MgL22 + (NMe4)[L2] ((NMe4)[MgL23]), and (d)
ZnL22 + (NMe4)[L2] ((NMe4)[ZnL23]) in CDCl3 at 30 C.
°
Chart 2 Possible structures of [ML13]− (M = Mg, Zn).
Based on the X-ray structures of MgLn2, reasonable models
were constructed and geometrically optimized using DFT
calculations at the B3LYP/6-31G(d,p) level. The optimized
structures for two isomers are shown in Fig. S8.† The
converged total energy of fac-[MgL13]−, with an approximately
three-fold rotational symmetry, was lower than that of mer-
Fig. 7 Time course for the hydrolysis of TNPP by MLn2
(M = Mg, Zn; n = 1, 2) or
−
by ~ 15 kcal mol−1. In fac-[MgL13]−, three Ar3C
Ca2L14 in CD2Cl2 at 50
°
C monitored by 1H NMR spectroscopy.
[
MgL13
]
groups adequately cover the facial Mg(H2O)3 site to prevent
another coordination and each coordinated water molecule
forms an intramolecular OH···O=C hydrogen bond with the
uncoordinated oxygen atom of a neighboring carboxy group. A
trial to isolate (NMe4)[MLn3] by recrystallization failed due to
the undesired (NMe4)[Ln] crystallizing first. Such dissociation
should occur in solution as described below.
Contributions of NH···O hydrogen bonds
The contributions of NH···O hydrogen bonds are illustrated in
Fig. 8. The direct hydrogen bond to the coordinated oxygen
atom of the carboxy group elongates the M–O (carboxylate)
bond and shortens the M–OH2 bonds. On the other hand, the
hydrogen bond to the uncoordinated oxygen atom has the
opposite effect. The strong M–OH2 bond resulted in a relatively
Hydrolysis of TNPP by metal carboxylates in nonpolar solvents
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high acidity of the coordinated water, which was evaluated by
the H NMR spectra. The hydrolytic activities are in the same
Conclusions
1
Soluble magnesium and zinc carboxylates containing
intramolecular NH···O hydrogen bonds in nonpolar solvents,
e.g. toluene, dichloromethane, and chloroform, were
synthesized and their structures were determined. These
order of the strength of the M–O (carboxylate) bonds for the
same metal ion, which suggests that the basicity of the OH−
group, rather than the acidity of OH2 group, is the essential
factor for achieving high reactivity.
complexes were mononuclear [M(Ln)2(H2O)4] (M = Mg, Zn;
n
=
1, 2
) and crystallized in the trans or cis configuration,
although the analogous calcium complex had a dinuclear
structure. The M–O (carboxylate) and M–OH2 distances were
regulated by the NH···O hydrogen bonds, depending on the
mode, as reported previously.23 The 1H NMR signals were very
broad in nonpolar solvents and suggested a fast trans-cis
isomerization on the NMR timescale. The NMR spectroscopic
measurements revealed the acidity of the coordinated water in
solution. Equimolar addition of Ln− ions sharpened the broad
signals clearly, indicating the formation of
tris(carboxylate) complex, fac-[MLn3]−.
a unique
Fig. 8 Contributions of the intramolecular NH···O hydrogen bonds to M–O bonds,
acidity of the coordinated water, and hydrolytic activity of phosphoric ester.
Acknowledgements
This work was supported by JSPS KAKENHI (Grant No.
26410072).
Reaction mechanism of the hydrolysis
In the previous paper, we described a proposed mechanism for
the hydrolysis in both inner-sphere and outer-sphere
pathways.27 To confirm the interaction between ML22 and
TNPP in solution, the 1H NMR spectra of ZnL22 in the
Notes and references
Department of Macromolecular Science, Graduate School of Science,
Osaka University, Toyonaka, Osaka 560-0043, Japan.
E-mail: tokamura@chem.sci.osaka-u.ac.jp; Fax: +81 6 6850 5474; Tel:
presence and absence of TNPP were measured. The signals of +81 6 6850 5451
† Electronic Supplementary Information (ESI) available: X-ray
the ligand became slightly sharp with negligible shifts. The
signals of TNPP were not affected by ZnL22 in CDCl3.
However, the signal of the coordinated water molecule was
shifted upfield by 0.32 ppm, suggesting the presence of
intermolecular interactions. The 31P NMR spectrum of TNPP
crystallographic data for L0H, (NMe4)[L1], L2H, Ca2L14
,
MgL12(EtOH), and MgL22(EtOH), molecular structures, 1H NMR
spectra, and optimized structures of [MgL13]−. CCDC 1042059—
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,
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Because the amount of the intermediate is probably small, an
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Dalton Transactions
View Article Online
DOI: 10.1039/C5DT00053J
Magnesium and zinc carboxylates containing intramolecular NH···O hydrogen bonds showed a fast trans-cis
isomerization in nonpolar solvents and were converted into anionic tris(carboxylate)s by the addition of equimolar
ligand.