Unusual Ionic Bond and Solubility Mechanism of NanPQQ (n = 0-4) Crystals

Article abstract of DOI:10.1021/acs.cgd.7b00324

A comparative study of van der Waals and ionic crystals can provide vital information for the medical and food industries. In this work, we investigated the coenzyme pyrroloquinoline quinone (PQQ), which contains three carboxyl groups coupled to imidazole, pyridine, and quinone. Whole-crystal analysis (crystal-ome) was attempted for Na_nPQQ (n = 0-4) crystals. All deprotonation sites were found to be dependent on pK_a except for the Na sites, which cannot be explained by pK_a. The Na₁PQQ crystal exhibited an unusual ionic bond, forming COOH-Na⁺ at one of the carboxyl sites in the structure. The difference in the solubility of the van der Waals and ionic crystals was also investigated, with a focus on the dissolution processes of Na₀PQQ and Na₂PQQ, by combining molecular dynamics simulations with experiments that define the crystal surfaces. This study is the first step toward developing a general rule to link the different types of crystal structures with different dissolution mechanisms and rates.

Full text of DOI:10.1021/acs.cgd.7b00324

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Article
Unusual ionic bond and solubility mechanism of NanPQQ (n = 0–4) crystals
Kazuto Ikemoto, Yuki Sakamoto, Rikako Tanaka, Koji Ogata, Nobuyuki Matsushita, and Shinichiro Nakamura
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00324 • Publication Date (Web): 03 Jul 2017
Downloaded from http://pubs.acs.org on July 6, 2017
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Unusual ionic bond and solubility mechanism of Na PQQ (n
n
=
0–4) crystals
†
*
‡,§,⊥
‖,∇
‡
Kazuto Ikemoto , Yuki Sakamoto
Rikako Tanaka , Koji Ogata , Nobuyuki
,
‖,∇
‡,§,*
Matsushita , Shinichiro Nakamura
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ABSTRACT: A comparative study of van der Waals and ionic crystals can provide vital information for the
medical and food industries. In this work, we investigated the coenzyme pyrroloquinoline quinone (PQQ),
which contains three carboxyl groups coupled to imidazole, pyridine, and quinone. Wholeꢀcrystal analysis
(
crystalꢀome) was attempted for Na PQQ (n = 0–4) crystals. All deprotonation sites were found to be
n
dependent on pK except for the Na sites, which cannot be explained by pK . The Na PQQ crystal exhibited an
a
a
1
+
unusual ionic bond, forming COOH–Na at one of the carboxyl sites in the structure. The difference in the
solubility of the van der Waals and ionic crystals was also investigated, with focus on the dissolution processes
of Na PQQ and Na PQQ, by combining molecular dynamics simulations with experiments that define the
0
2
crystal surfaces. This study is the first step towards developing a general rule to link the different types of
crystal structures with different dissolution mechanisms and rates.
†
* Niigata Research Laboratory, Mitsubishi Gas Chemical Co., Inc., 182 Tayuhama, Shinwari, Kitaꢀku,
Niigata 950ꢀ3112, Japan, Phone +81ꢀ25ꢀ258ꢀ8081, Fax +81ꢀ25ꢀ259ꢀ8288, kazutoꢀikemoto@mgc.co.jp
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Unusual ionic bond and solubility mechanism of
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Na PQQ (n = 0–4) crystals
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Kazuto Ikemoto , Yuki Sakamoto ⊥, Rikako Tanaka‖,∇, Koji Ogata , Nobuyuki Matsushita
†
*
‡,§,
‡
‖,∇
‡,§,*
Shinichiro Nakamura
,
† Niigata Research Laboratory, Mitsubishi Gas Chemical Co., Inc., 182 Tayuhama, Shinwari,
Kitaꢀku, Niigata 950ꢀ3112, Japan
‡ Research Cluster for Innovation, Nakamura Laboratory, RIKEN, 2ꢀ1, Hirosawa, Wako,
Saitama 351ꢀ0198, Japan
§ Computational Chemistry Applications Unit, Advanced Center for Computing and
Communication, RIKEN, 2ꢀ1, Hirosawa, Wako, Saitama 351ꢀ0198, Japan
⊥ Department of Biological Information, Tokyo Institute of Technology, 4259 Nagatsuta,
Midoriꢀku, Yokohama 226ꢀ8501, Japan
‖
Department of Chemistry, College of Science, Rikkyo University, 3ꢀ34ꢀ1 NishiꢀIkebukuro,
Toshimaꢀku, Tokyo 171ꢀ8501, Japan
∇ Research Center for Smart Molecules, Rikkyo University, 3ꢀ34ꢀ1 NishiꢀIkebukuro, Toshimaꢀ
ku, Tokyo 171ꢀ8501, Japan.
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KEYWORDS PQQ, Solubility, Na, ionic bond, van der Waals
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ABSTRACT
A comparative study of van der Waals and ionic crystals can provide vital information for the
medical and food industries. In this work, we investigated the coenzyme pyrroloquinoline
quinone (PQQ), which contains three carboxyl groups coupled to imidazole, pyridine, and
quinone. Wholeꢀcrystal analysis (crystalꢀome) was attempted for Na PQQ (n = 0–4) crystals. All
n
deprotonation sites were found to be dependent on pK except for the Na sites, which cannot be
a
+
explained by pK . The Na PQQ crystal exhibited an unusual ionic bond, forming COOH–Na at
a
1
one of the carboxyl sites in the structure. The difference in the solubility of the van der Waals
and ionic crystals was also investigated, with focus on the dissolution processes of Na PQQ and
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Na PQQ, by combining molecular dynamics simulations with experiments that define the crystal
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surfaces. This study is the first step towards developing a general rule to link the different types
of crystal structures with different dissolution mechanisms and rates.
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INTRODUCTION
The solubility of organic crystals is a pertinent problem in the pharmaceutical and food
industries. The study of crystal structures is central to better understanding, and therefore
controlling this parameter. Many pharmaceutical studies have investigated the relationship
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between crystal structure and solubility. However, few have discussed the direct link between
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the arrangements of molecules in the crystal packing and the dissolution process. Indeed, only
a handful of studies pertaining to crystal growth discuss the dissolution process of organic
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crystals. In light of this gap in our understanding, we investigated the difference in solubility
between van der Waals and ionic crystals of the same molecular framework.
The work focused on pyrroloquinoline quinone (PQQ; 4,5ꢀdihydroꢀ4,5ꢀdioxoꢀ1Hꢀpyrrolo[2,3ꢀf]
quinolineꢀ2,7,9ꢀtricarboxylic acid) (Figure 1(a)). PQQ was originally discovered as a cofactor of
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bacterial dehydrogenases.
Subsequently, several studies sought to investigate the effect of
PQQ on mammalian processes such as metabolism. In 2004, it was proposed that PQQ was a
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new vitamin. PQQ disodium is now commonly taken as a supplementary vitamin in the US and
Japan owing to the reported health benefits associated with its ingestion, such as treatment of
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hypoglycemia, mitochondrial activation, and improvement of brain function.
More recently,
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it was reported that PQQ even works as an organic catalyst. PQQ consists of imidazole,
pyridine, and quinone groups coupled to three carboxyl groups. Each carboxyl group has a
different pK , which implies that each carboxyl group has a different dissociation form
a
dependent on the pH. The range of uses and structural characteristics outlined above provided
the impetus behind our choice of PQQ as a model compound with which to study the solubility
in van der Waals and ionic crystals. In this study, Naꢀstoichiometryꢀdependent crystals have been
+
investigated. The structural characteristics of ionic PQQ crystals, which contain Na ions in the
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crystal packing structure (Na PQQ, n = 1, 3, 4), and van der Waals PQQ crystals (Na PQQ) were
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compared, and the different dissolution processes of these structures were analyzed.
In addition to the two types of Na PQQ crystal structures that have already been reported,
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various Na PQQ (n = 0, 1, 3, 4) structures were crystallized and analyzed.
The difference
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between the Na or H coordination positions within the crystal structures and molecular packing
has been discussed. The dissolution processes of Na PQQ and Na PQQ in water and artificial
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gastric juice have also been compared. The results of these studies, reported here for the first
time, provide insight into the relationship between the dissolution rate and the anisotropy of
organic crystals. Thus, this work provides a crucial first step towards a general rule linking the
crystal structure to dissolution.
EXPERIMENTAL SECTION
Elemental analyses were performed using a Thermo Finnigan FLASH EA1112 system.
BioPQQ®, the product name of disodium pyrroloquinoline quinone trihydrate, was obtained
from Mitsubishi Gas Chemical Co., Ltd. and other materials were obtained from Wako
Chemicals.
Preparation and crystallization of Na PQQ (free form) A 200 mL aqueous solution was
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prepared by mixing Na PQQ (2.0 g) with conc. HCl (3.6 g) and stirring for 18 h. The resultant
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red powder (1.6 g) was filtered. The red powder (1.0 g) was mixed with water (1 L) and heated at
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20 °C. Subsequently, 2 N HCl (10 mL) was added to the solution at 70 °C, which was then left
to stand for 4 days while the red crystalline product precipitated.
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Crystallization of Na PQQ-A Na PQQ (50 mg) was dissolved in 15 mL of aq. gastric juice
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analogue (15 g of NaCl and 7 mL of conc. HCl in 1 L of water). After 4 days, the red crystal was
precipitated at 4 °C.
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Crystallization of Na PQQ-B Na PQQ (50 mg) was mixed with same amount HCl in water
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(10 mL) at 70 °C. After 1 day, the red crystal was precipitated.
Crystallization of Na PQQ Na PQQ was prepared by adding NaCl to a pH 7.5 phosphate
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buffer solution of Na PQQ. An aqueous solution of Na PQQ 20 mg (7 mL) was mixed with 0.3
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mL of a 15% NaCl/water solution. After a few days, the crystal was precipitated at room
temperature.
Preparation and crystallization of Na PQQ An aqueous solution (0.5 mL) of Na PQQ (1 mg)
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and 0.1 mL of 25 wt% aq. NaOH were mixed. At this time, the pH was 13.4. Methanol (1 mL)
was slowly added to the mixture and the solution was left to stand at room temperature for 4 days
until the red crystal product was precipitated.
Quantum chemical calculations Quantum chemical calculations were performed by using
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density functional theory (DFT) with the B3LYP hybrid functional.
For the crystal structure
analysis, the 6ꢀ31G (d,p) basis set was used. The XRD structure was used as the input geometry
without any optimizations. For population analysis, we performed natural bond orbital (NBO)
analysis. The DFT calculations and natural orbital analysis were performed using the Gaussian
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09 program package.
RESULTS AND DISCUSSION
Crystals
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The previously reported Na PQQ crystals are Na PQQ trihydrate
and Na PQQ
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pentahydrate, which contain three and five crystal waters in a unit cell, respectively. Na PQQ
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trihydrate was used as the starting material. Other Na PQQ crystals were prepared by replacing
n
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the Na by adding HCl (Na PQQ), solvating Na PQQ in the artificial gastric juice (Na PQQꢀA)
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at 4 °C, Na PQQꢀB with HCl at 70 °C, and controlling the pH of the solution (7.5 for Na PQQ
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and 13.4 for Na PQQ). Na PQQ have two types (A, B) by temperature (4 and 70 °C).
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Structural features of the carboxyl groups.
Table 1 shows a summary of the protonated forms of each carboxyl group and the number of
crystal water molecules in a unit cell. Crystal structural analyses revealed that all Na PQQ (n =
n
0–4) molecules adopt the same molecular frame (Figure 1). However, upon close inspection,
there are some small but crucial differences. First, the dihedral angles of the carboxyl groups
vary greatly, particularly for the group labelled C13. Second, the number of crystal water
+
molecules increases with the increasing number of Na ions present in the unit cells. It is also
−
noteworthy that each of the carboxyl groups forms either COOH (protonated), COO
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+
(deprotonated), or COONa (binding Na ). The Na coordinating position in each crystal was
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analyzed based on pK values, which were obtained from the literature. Density functional
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theory (DFT) calculations were performed to assign the pK values for each carboxyl and pyrrole
a
group (see Supplementary Information). These calculations revealed that the C13 (Figure 1)
carboxyl group has the lowest pK value, followed by the carboxyl groups labelled C12 and C14
a
and the pyrrole group labelled N1.
The extent to which the carboxyl groups bind to a proton is dominated by the pK of each
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group. Thus, it is expected that a carboxyl group with a low pK value exists as COO or that it
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will form COONa in the presence of Na in a crystal structure. Indeed, the C13 carboxyl group
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its protonated form as COOH. The carboxyl groups C12 and C14 are coordinated to Na in this
crystal structure. This result may be due to the crystallization being performed in the presence of
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alcohols.
Considering the pK values of each carboxyl group alone is not sufficient to explain why some
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groups exist as COO and others as COONa in these crystal structures. For example, in the
Na PQQ pentahydrate crystal structure, all carboxyl groups exist in their deprotonated form,
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COO . Furthermore, the most acidic carboxyl group (C13) in the Na PQQꢀA crystal structure
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exists in its deprotonated form (COO ) rather than in the Na ꢀcoordinated form (COONa). In
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cations present in the solution may also play a role in determining which state the carboxyl
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groups will be in for each structure. That is, for any one structure, the coordination of Na to
each carboxyl group may be affected by the crystallization conditions. This question pertaining
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to the position of Na will be investigated in a future study.
Na PQQ-A crystal structure
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The crystal structure of Na PQQꢀA is quite unique. Na PQQꢀA forms a dimeric structure
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+
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where two PQQ ions share two Na ions (Figure 1b). The C13 group exists in its COO form,
+
whereas Na coordinates to the oxygen atom labelled O4 (Figure 1b) in the protonated C12
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carboxyl group. Na also coordinates to the nitrogen atom labelled N1 in the pyridine group and
to the oxygen atom labelled O2 in the quinone group (Figure 1b). Despite the pK arguments
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In order to better understand the observed crystal structures, DFT calculations were performed.
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(
Na PQQ) was used as an input structure and a population analysis was performed. Natural
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bonding analysis was used to determine the atomic charges of the atoms surrounding Na (as
+
described in Figure 2), all of which were found to be negative. The Na environment observed is
2
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reminiscent of a crown ether. Such structural features are typical for ionic bonds. Therefore, it
+
−
can be concluded that the bond between Na and PQQ is purely ionic with almost zero covalent
+
bond character. This structure is centrosymmetric with two Na ions and is held together solely
by electrostatic attraction. It is remarkable that an undissociated carboxyl group can bind to a
+
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Na ion in this manner. This is consistent with the reports of crystal structures in which Na also
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coordinates to undissociated carboxyl groups, such as in sodium hydrogen maleate trihydrate.
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However, there are still very few examples in the literature of such behavior.
Solubility
Na PQQ and Na PQQ trihydrate were selected to investigate the solubility and dissolution
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processes of van der Waals and ionic PQQ crystals, respectively. First, the saturated solubility of
each was measured. The ionic crystal Na PQQ showed significantly higher solubility as
2
compared to the Na PQQ van der Waals crystal over a range of pH values (Table 2). This
0
difference was maintained when the saturated solubility of the two structures was measured in a
buffer solution. The saturated solubility of a structure is related to several factors such as its
lattice energy, solvation energy, and ionization energy. The polarization of the PQQ may be a
factor that affects the lattice and solvation energies of its structures, hence perturbing the
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measured saturated solubility value. In order to further investigate the disparity in saturated
solubility between the two structures of the same molecular frame, the nature of each crystal was
considered. It is known that the larger the ionic radius of an ion, the smaller is its lattice energy.
It follows that when a structure has a high lattice energy, it will have low solubility. Because the
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to have the larger ionic radius of the two. Thus, it is expected that the Na PQQ crystal structure
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structure.
2−
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Dissolution of ions having larger valences (X , X …) may be favorable as a result of their
large solvation energies. Because a PQQ molecule has three carboxyl groups, the resulting anion
can be trivalent at most. Therefore, the barrier to multivalence may explain the measured
+
solubility difference between the Na PQQ and Na PQQ crystals. Na ions coordinate to the C12
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and C14 carboxyl groups of the Na PQQ trihydrate crystal. Thus, Na PQQ can easily become
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divalent in a solvent, irrespective of the pH. In solution, the most acidic C13 carboxyl group may
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deprotonate in solution to form COO . In contrast, all carboxyl groups present in the Na PQQ
0
structure form covalent bonds with hydrogen. Therefore, one can deduce that there is a lower
barrier to becoming a multivalent anion for Na PQQ as compared to Na PQQ. Thus, the ionic
2
0
structure would demonstrate a higher solubility than the van der Waals structure, which is
consistent with our observations.
Solvation process
The solvation process for the dissolution of the van der Waals crystal Na PQQ and the ionic
0
crystal Na PQQ were compared. Both crystals were placed in an artificial gastric juice (HCl +
2
NaCl) solution of pH 1.2 and the concentration of the PQQ anions liberated into solution was
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monitored as a function of time. The results for Na PQQ and Na PQQ are shown in Figure 3(a)
0
2
and 3(b), respectively. It is apparent from the data that Na PQQ has a higher solubility than
2
Na PQQ. It is also particularly clear when comparing the beginning of each experiment. As both
0
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crystals have the same molecular framework, these results indicate that the molecular properties
of each crystal affect the solubility. That is, the strength of crystal packing and ionicity of each
structure affects the rate of dissolution.
We repeated the dissolution experiments described above in water and observed the change in
the shape of each crystal through an optical microscope, the results of which are shown in Figure
3(c) and 3(d) for the van der Waals and ionic crystals, respectively. The volume and shape of the
van der Waals crystal, Na PQQ, did not change after soaking. Conversely, a large section of the
0
Na PQQ crystal dissolved within 5 min of soaking. Notably, the length of the longest side of the
2
crystal did not change relative to the other sides, which indicates that the surfaces of the Na PQQ
2
structure have varying solubility. In order to further understand this observation, the molecular
orientation in the unit cells of each crystal was determined and the surface indices were
measured. The results are shown in Figure 3(e) and 3(f) for Na PQQ and Na PQQ, respectively.
0
2
The longest side of the ionic crystal observed through the optical microscope was assigned to the
2
−
aꢀaxis in the Na PQQ unit cell. As PQQ anions stack along the aꢀaxis in the Na PQQ crystal
2
2
structure, the results indicate that exfoliation along the aꢀaxis is difficult as compared to the other
axes of the crystal. Conversely, when observing the dissolution of Na PQQ in water, it was
0
found that the crystal dissolved slowly and in an isotropic manner. This may be attributed to the
staggered structure of the crystal and the covalent bonds between the carboxyl groups and
protons. The surfaces of the van der Waals crystal are hydrophobic, which may explain the slow,
isotropic dissolution of this crystal in water. Thus, one can infer that the dissolution process
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depends on the polarization of the crystal (i.e., ionic or van der Waals), surface orientation, and
packing.
Molecular dynamics (MD) simulations were employed to further investigate the dissolution
processes described above and to better understand our observations. The possible mechanism of
dissolution can be studied by monitoring the simulated movement of ions, which cannot be
observed via an experimental microscope. The MD simulations were performed on systems that
contained each crystal lattice in the TIP3P water box (see Supporting Information for further
0
1
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9
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details). The 250 ns MD simulation showed that the ionic Na PQQ crystal underwent anisotropic
2
dissociation. While dissolution along the aꢀaxis was not observed, it instead took place along the
axis normal to the aꢀaxis. The calculated results from the 250 ns MD simulation matched those
observed experimentally through the optical microscope. However, Na PQQ dissolution was not
0
observed in the time frame of the 250 ns MD simulation. When comparing MD simulations to
experimental results, the vastly different time and space scales of the two techniques must
always be considered. Thus, further studies are required to definitively understand the observed
dissolution behavior. Nevertheless, the MD simulations indicate that the two types of crystal,
Na PQQ and Na PQQ, undergo distinctly different dissolution processes. The similarity in the
0
2
calculated dissolution of the ionic crystal compared to what has been observed is stark.
The simulations and experiments discussed in this paper provide insights into the different
dissolution processes of a van der Waals crystal and an ionic crystal of the same molecular
framework. Combining macroscopic observations with MD simulations has provided an
explanation for the enhanced dissolution process of Na PQQ relative to Na PQQ, as shown in
2
0
Figure 4. The results presented in this paper indicate that
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(
i) Na ions located near the corner of a crystal structure dissociate first. If the dissociating
+
−
Na is a bridge between the PQQ ions, then repulsion within the structure increases.
−
(
ii) PQQ ions then begin to dissociate from the structure.
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Here, we present an explanation for the link between crystal properties and dissolution. This
study provides insight into how crystal structures can be designed to manipulate their dissolution
behavior. Further surface measurement studies are being performed in our group.
CONCLUSIONS
A new concept in crystallography has been suggested. Whole crystal analysis (crystalꢀome) of
Na PQQ (n = 0–4) arrived at two important results. First, the deprotonation of almost all sites
n
depends on the pK . However, Na sites cannot be explained by pK . In fact, the Na PQQꢀA
a
a
1
+
crystal exhibited an unusual ionic bond forming COOHꢀNa at one of the carboxyl sites in the
structure. Second, the study and comparison of the solubility of van der Waals and ionic crystals
is vital information for medical and food industries. The difference in the solubility between the
van der Waals and ionic crystals was investigated. The dissolution processes of Na PQQ and
0
Na PQQ were also studied by combining molecular dynamics simulations with experiments that
2
define the crystal surfaces. This study is the first step towards developing a general rule to link
types of crystal structure with different dissolution mechanisms and rates.
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Figure 1 Molecular structures of the Na PQQ (n = 0–4) crystals. Atoms colored in green, red,
blue, grey, and white are sodium, oxygen, nitrogen, carbon, and hydrogen respectively.
Displacement ellipsoids are drawn at the 50% probability level for nonꢀH atoms.
n
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(
[
2
a) Na PQQ, (b) Na PQQꢀA, (c) Na PQQꢀB, (d) Na PQQ, (e) Na PQQ, (f) Na PQQ
0 1 1 2 3 4
Symmetry code: (i) –x, y, 1/2−z, (ii) −1+x, −1+y, z, (iii) x, y, 1+z, (iv) –x, 2−y, 1−z, (v) 1/2−x,
−y, 1/2+z.]
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Figure 2 Environment around Na in the Na PQQꢀA crystal structure. The values in red color
1
are the atomic charges obtained from natural orbital analysis. The values in black color are the
distances between Na and each of the surrounding atoms.
+
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Figure 3 The solubility of (a) Na PQQ and (b) Na PQQ in gastric juice as a function of time.
0
2
Microscopic observations of dissolution of (c) Na PQQ and (d) Na PQQ crystals. Molecular
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orientation viewed along the bꢀaxis of (e) Na PQQ and (f) Na PQQ.
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the structure dissociate first. (ii) PQQ ions begin to dissociate from the cluster.
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Table 1. Structural summary of Na PQQ crystals.
n
O
C
OH
1
4
HO
O
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1
3
C
N
HN
b
HO 12
C
O1
O
O2
Acidic site
Quinone
Py
C12
(pK 2.2)
C13
(pK 1.6)
C14
N
(pK 3.3)
(pK 10.4)
O1
O2
N
a
a
a
a
n
m
φ
φ
φ
0
1
1.3(2)
COOH
8.9(2)
COOH
6.9(2)
COOH
COOH
NH
ꢀ
ꢀ
ꢀ
−
1ꢀA
4
2
3
10.2(2) COOHꢀNa
1.69(2) COOHꢀNa
28.9(2)
28.0(2)
51.7(2)
34.4(2)
30.7(2)
COO
9.6(2)
NH
NH
NH
NH
NH
OꢀNa
OꢀNa
OꢀNa
OꢀNa
ꢀ
OꢀNa
ꢀ
NꢀNa
NꢀNa
NꢀNa
NꢀNa
NꢀNa
1
ꢀB
COOꢀNa
COOH
10.3(2) COOHꢀNa
5.9(2) COOꢀNa
c
2
8.6(2)
COOꢀNa
COOꢀNa
COOꢀNa
OꢀNa
OꢀNa
OꢀNa
8
.59(6)
COOꢀNa
COOꢀNa
3.79(5) COOHꢀNa
8.75(4) COOHꢀNa
d,e
2
5
7.90(4)
−
3
4
6
2.1(5)
COOꢀNa
COOꢀNa
24.0(2)
COO
6.1(3)
COOꢀNa
COOꢀNa
NH
OꢀNa
ꢀ
OꢀNa
OꢀNa
NꢀNa
NꢀNa
8.5 3.12(3)
87.49(5)
COOꢀNa
6.35(3)
NꢀNa
a
Dihedral angles and the coordination states of the functional groups in Na PQQ•m(H O). The
n
2
19 b
pK for each carboxyl group has been noted.
φ indicates dihedral angles of two leastꢀsquares
a
−
c
d
e
2−
planes defined by N1,N2/C1ꢀC11 and COO . Ref. 14. Ref. 15. In this crystal, PQQ ions
exist in two conformations.
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Table 2 The solubility of ionic Van der Waals crystal (Na PQQ) and crystal (Na PQQ) in
0
2
several solvents.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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Na PQQ
Na PQQ
0
2
−3
−1
−3
−1
(
10 mol L )
(10 mol L )
9.69
Water
0.93
Artificial gastric juice
(
pH = 1.2)
Artificial intestinal juice
pH = 6.8)
0.03
1.85
0.24
(
22.84
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental details, CIF data.
AUTHOR INFORMATION
Corresponding Author
*
*
kazutoꢀikemoto@mgc.co.jp (KI)
snakamura@riken.jp (SN)
Author Contributions
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K.I.: Chemical experiments, R.T. and N. M.: crystallography, Y. S., K.O. and S. N.: Physical
chemistry (computer)
Notes
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the HOKUSAI Greatwave of RIKEN for computational resources.
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REFERENCES
1) Tawashi, R., Science 1968, 160, 76.
(
(2) Watanabe, A.; Yamaoka, Y.; Takada, K., Chem. Pharm. Bull. 1982, 30, 2958ꢀ2963.
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(3) Tamura, R.; Fujimoto, D.; Lepp, Z.; Misaki, K.; Miura, H.; Takahashi, H.; Ushio, T.;
Nakai, T.; Hirotsu, K., J. Am. Chem. Soc. 2002, 124, 13139ꢀ13153.
(4) Coquerel, G., In Advances in Organic Crystal Chemistry, Tamura, R.; Miyata, M., Eds.
Springer Japan: Japan, 2015; chapter 20, pp 393ꢀ420.
(
5) Uchida, Y.; Iwama, S.; Coquerel, G.; Tamura, R., Chem. Eur. J. 2016, 22, 11660ꢀ11666.
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(
(7) Duine, J.; Van Zeeland, J., FEBS Lett. 1979, 108, 443ꢀ446.
(8) Salisbury, S.; Forrest, H.; Cruse, W.; Kennard, O., Nature 1979, 280, 843ꢀ844.
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(12) Takada, M.; Sumi, M.; Maeda, A.; Watanabe, F.; Kamiya, T.; Ishii, T.; Nakano, M.;
Akagawa, M., Biochem. Biophys. Res. Commun. 2012, 428, 315ꢀ320.
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(
13) Uchida, W.; Wakabayashi, M.; Ikemoto, K.; Nakano, M.; Ohtani, H.; Nakamura, S.,
Chem. Phys. Lett. 2015, 620, 13ꢀ18.
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15) Ishida, T.; Doi, M.; Tomita, K.; Hayashi, H.; Inoue, M.; Urakami, T., J. Am. Chem. Soc.
1
989, 111, 6822ꢀ6828.
(16) Becke, A. D., Phys. Rev. A 1988, 38, 3098ꢀ3100.
(17) Becke, A. D., J. Chem. Phys 1993, 98, 5648ꢀ5652.
(
(
(
18) Hohenberg, P.; Kohn, W., Phys. Rev. B 1964, 136, B864ꢀB871.
19) Lee, C.; Yang, W.; Parr, R., Phys. Rev. B 1988, 37, 785ꢀ789.
20) Frisch, M.; Trucks, G.; Schlegel, H.; Scuseria, G.; Robb, M.; Cheeseman, J.; Scalmani,
G.; Barone, V.; Mennucci, B.; Petersson, G., Gaussian 09, revision D. 01. In ed.; Gaussian, Inc.,
Wallingford CT: 2009.
(21) Zhang, Z.; Tillekeratne, L.; Kirchhoff, J. R.; Hudson, R. A., Biochem. Biophys. Res.
Commun. 1995, 212, 41ꢀ47.
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22) Pedersen, C. J., J. Am. Chem. Soc. 1967, 89, 7017ꢀ7036.
23) Guo, M.ꢀL., Acta Crystallogr. Sect. Sect. E: Struct. Rep. Online 2004, 60, m1684ꢀm1685.
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Commun. 1984, 40, 1521ꢀ1526.
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Crystal Growth & Design
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For Table of Contents Use Only
Unusual ionic bond and solubility mechanism of Na PQQ (n = 0–4) crystals
n
Kazuto Ikemoto, Yuki Sakamoto, Rikako Tanaka, Koji Ogata, Nobuyuki Matsushita,
Shinichiro Nakamura
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Wholeꢀcrystal analysis (crystalꢀome) is applied to Na PQQ (n = 0–4). While the deprotonation
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sites are dependent on the pKa value, the location of Na cannot be explained by pKa. Na PQQ
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exhibited an unusual ionic bond COOH–Na . The difference in the solubility of the van der
Waals (Na PQQ) and ionic (Na PQQ) crystals is explained by a combination of molecular
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dynamics simulations and experiments that define the crystal surfaces.
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