Article pubs.acs.org/crystal
Deuterium Shifts the Equilibrium: How Heavy Water Can Influence Organic Multicomponent Crystal Formation Dennis D. Enkelmann,† Detlef W. M. Hofmann,*,‡ and Klaus Merz*,† †
Inorganic Chemistry I, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany CRS4, Loc. Piscina Manna 1, 09010 Pula, Cagliari, Italy
‡
Crystal Growth & Design 2017.17:4726-4729. Downloaded from pubs.acs.org by DURHAM UNIV on 09/05/18. For personal use only.
S Supporting Information *
ABSTRACT: The use of heavy water as solvent in the reaction of oxalic acid with pyridine enables the approach to an alternative crystalline product formation compared to the analogues’ reaction in water. The thermodynamically driven molecular aggregation is heavily influenced by the shifted strength of intermolecular interactions, induced by the hydrogen/deuterium exchange.
T
D2O can be used for targeted control of reaction processes. Conditioned by the higher self-aggregation12,13 and the lower dissociation constant of D2O, weak acids show a lower pKa value in heavy water than in nondeuterated water.14 Dependent on the degree of acidity alternating pKa shifts are observed. Solvation dynamics are also influenced by using D2O instead of H2O. Studies of methyl-β-cyclodextrin by Sasmal et al. revealed a reduction in solvation velocity of 25% in D2O solution, comparable to insights into solvation dynamics of nanoscale ZrO2 particles in D2O solution.15,16 The presented model reaction, regarding aggregation behavior of pyridine and oxalic acid, shows formation of two different products depending on the use of water or heavy water.
he role of deuterium in molecular evolution and in chemical processes has increased in the recent years.1 Substitution of H2O by D2O is generally not seen as an influencing parameter in relation to reaction thermodynamics and product formation.2,3 Hydrogen/deuterium (H/D) exchange can be seen as the smallest possible exchange of an element on a molecule. The only isotope that has its own symbol is deuterium. It influences physical and chemical properties which directly correlate with the nature of the hydrogen/deuterium atom. This effect is used in kinetic studies (kinetic isotope effect) and in vibrational and NMR studies. An evaluation in terms of molecular crystals, using the Born− Oppenheimer approximation, generally predicts no influence on the potential surface. It is expected that molecular aggregation in a crystal is not affected by H/D substitution. Nevertheless, this assumption is not supported by comparing the aggregation of several deuterated and nondeuterated compounds.4−7 Instead even the comparison of H2O and D2O reveals alternations in strength and number of existing hydrogen bonds.8,9 This leads to deviations of melting and boiling points and the temperature of maximum density (D2O 11.22 °C and H2O 4.08 °C).10 In contrast to covalent bonds, which show electron pairing, hydrogen bonds show group properties. Their energies and geometries are functions of the hydrogen bond pattern in the solid state. Molecular surrounding, solvation, and ion radii influence those patterns and therefore also the whole hydrogen bond network in the crystal lattice. Hughes and Harris showed that substitution of water by heavy water can influence the formation of polymorphic modifications of the amino acid glycine.11 However, the impact of heavy water is not limited to the formation of isotopic polymorphs. Because of its deviating properties from H2O, © 2017 American Chemical Society
Up to now, crystalline pyridinium oxalate and pyridinium hydrogen oxalate ([Hpy+]·[Hox−]) compounds have been obtained as cocrystalline salts together with oxalic acid (H2ox) Received: May 8, 2017 Revised: June 23, 2017 Published: July 17, 2017 4726
DOI: 10.1021/acs.cgd.7b00654 Cryst. Growth Des. 2017, 17, 4726−4729
Crystal Growth & Design
Article
from solution.17−19 For example, the cocrystalline salt hydrate H2ox·Hox−·Hpy+·2H2O (1) was synthesized by crystallizing oxalic acid dihydrate from a water/pyridine mixture in the presence of L-proline.19
Figure 2. Molecular arrangement of (2) Dox−·Dpy+·2D2O in the solid state and scheme. Figure 1. Molecular arrangement of 1 H2ox·Hox−·Hpy+·2H2O in the solid state and scheme.19
In contrast, the crystal structure of 2 contains a weaker hydrogen bond between the pyridinium cation and the carboxylate group in the anion, which is asymmetric and no longer bifurcated (dO···N = 2.78 Å). Stronger hydrogen bonds with electrostatic character connect hydrogen oxalate molecules to a linear chain. The most remarkable change in the solid state structure of 2 compared to 1 (where H2O is part of the zigzag network) is the unusual aggregation of the D2O molecules in tetrameric domains. Theoretical Approach. Independent of the concentration of the solutions both reactions lead only to products 1 and 2. Consequently, it can be assumed in both cases that there is an equilibrium between both phases and the reactions are thermodynamically driven. In the case of hydrogen (X = H) this equilibrium is located on the right side of the scheme, whereas the reaction of the deuterated starting materials is shifted to the left.
First evidence for the influence of deuterated solvents on the reaction behavior of oxalic acid dihydrate and pyridine have been revealed by Lautie and Belabbes via vibrational spectroscopic methods.20 The fact that spectra of deuterated crystalline products deviated from those of the nondeuterated products has been interpreted by the authors as the appearance of different products. In our study per-deuterated starting materials, oxalic acid-d2· 2D2O and pyridin-d5, have been used to inhibit exchange reactions of hydrogen and deuterium atoms between substrate and solvent. The crystalline product obtained by direct reaction of oxalic acid and pyridine, without water as solvent, can be characterized as the salt Hox− · Hpy+. The analogous reaction using deuterated starting materials leads to an isostructural salt of the composition Dox−·Dpy+.21 However, once the solvent D2O is introduced into the reaction it does not lead to the expected product, which would be isostructural to the cocrystalline salt hydrate 1. According to the smallest possible change in the nature of the starting materials a completely new entity with another chemical and crystallographic composition is formed. In contrast to 1, the new crystalline product (from now on called 2) excludes the uncharged oxalic acid molecules from the crystal structure and consists of Dox−·Dpy+·2D2O.22 Crystallographic Interpretation. Comparison of the crystal structures of 1 and 2 shows not only a change of the molecular composition, but also a change in the network of intermolecular interactions. Compound 1 aggregates via strong hydrogen bonds between hydrogen-oxalate, oxalic acid, and water molecules in a zigzag pattern. The pyridinium cation completes the crystal structure with symmetric, bifurcated hydrogen bonds with a strong ionic character to one oxygen in the carbonyl group (dO···N = 2.93 Å) and one oxygen atom in the carboxylate group (dO···N = 2.89 Å), both in one hydrogen oxalate anion.
(2)
X 2ox aq + [Xox −·Xpy +·2X 2O]s X=H
(1)
HooooI [X 2ox· Xox −·Xpy +·2X 2O]s X=D
Interestingly, polar molecules show almost the same solubility in water and heavy water and thereby the same hydration energy. This is due to the fact that hydrogen bonds, which are broken to introduce the molecules to the aqueous matrix, are compensated by newly formed hydrogen bonds to the solvent.26 Therefore, the driving force for the formation of 1 and 2 can only have its origin in the molecular arrangement and intermolecular interactions in both crystal structures. To understand the competitive reactions, the molecule-pair interactions in the solid state have been analyzed (Table 1).23 It is conspicuous that the energetically dominating interaction [Dox−···Dox−] in 2 is also present in the nondeuterated structure of 1. However, in 1 it is insignificant compared to the other interactions (rank 12). The difference between interactions of deuterated and nondeuterated molecular crystals can be visualized by plotting frequency of occurrence of existing interactions (in the Cambridge Structural Database) against their distance. The dominating interactions, occurring in both structures 1 and 2, are [N−X···OC], [O−X···OC], and [>O···X-O]. In Figure 3, the frequency of the interaction [CO···O−X] is plotted as a function of its angle and distance. The maximum (red) for X = H is located at 2.75 Å and 170°. As shown in the scale, almost 16 000 compounds are known to be containing a hydrogen bond of the mentioned type. For the deuterated 4727
DOI: 10.1021/acs.cgd.7b00654 Cryst. Growth Des. 2017, 17, 4726−4729
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Nevertheless, it can be clearly seen that the hydrogen bonds show a much broader distribution compared to the deuterium bonds. For wide areas, the heat map for X = D shows empty space where no hydrogen bonding is observed in the database. In the first-order approximation, the occurring frequencies are connected to the Boltzmann distribution. Consequently, a lowered energetic minimum is implied for deuterium bonds. Concerning the lowering of the zero-point vibration, while in this study the effect is illustrated statistically, in previous studies we were able to prove it using a quantum mechanistic approach.5 A general discussion can be found at Scheiner and Cuma.27 Under estimation of a harmonic potential the zeropoint vibrational energy is correlated to the mass as follows:
Table 1. Calculated Intermolecular Potentials of the Dominating Intermolecular Potentials in the Crystal Structures of 1 and 2a (1) H2ox·Hox−·Hpy+·2H2O
(2) Dox−·Dpy+·2D2O
rank
interaction
energy
rank
interaction
energy
1 2 3 4 5 6 7 12 18 >20
Hox−···Hpy+ Hox−···H2O H2ox···H2O H2ox···H2O H2O···H2O Hpy+···Hpy+ H2ox···Hox− Hox−···Hox− Hox−···H2O H2O···H2O
−28.0 −27.7 −27.3 −23.1 −18.4 −13.3 −10.8 −8.8 −5.9 >−5.7
2 3
Dox−···Dpy+ Dox−···D2O
−22.8 −21.8
5 11
D2O···D2O Hpy+···Dpy+
−16.4 −8.4
1 4 6
Dox−···Dox− Dox−···D2O D2O···D2O
−24.7 −17.3 −15.4
E=
Hydrogens normalized. UNI force field calculations23 Xpy+ = pyridinium, Xox− = hydrogen oxalate, X2ox = oxalic acid.
a
h 4π
k μ
whereby k is the spring constant and μ the reduced mass. A third possibility is the analysis with force fields. We investigated the energy of formation with three different force fields (Table 2). The first method included the calculation of formation energies with effective Lennard−Jones potentials, which did not reveal any difference between hydrogen and deuterium.23 The positive formation energy could be interpreted as the reason for a slight, thermodynamically driven tendency toward decomposition of 1. The very low formation energy portends the influence of external effects like H/D substitution. The second method is based on a force field derived from the CSD using data mining.24 This force field works without the anticipation of a functional coherence and differentiates between hydrogen and deuterium. In fact, now it is observed that cocrystalline salt 1 is not formed when water is replaced by heavy water (ΔG = +17 kJ/mol > 0 kJ/mol). Eventually, we calculated the formation energy with a third force field that cannot differentiate between deuterium and hydrogen, but which splits the energy in coulomb and hydrogen bond interactions. This method reveals that the coulomb energy shifts the equilibrium toward formation of cocrystalline salt 1 (the right side) (−36 kJ/mol), whereas hydrogen bonds shift the equilibrium toward compound 2 (left side) (+18.5 kJ/mol). Table 2. Calculations of the Formation Energies of Cocrystalline Salt 1 from 2 and Oxalic Acid (unit: kJ/mol)
Figure 3. Frequency of CO···H−O contacts compared to frequency of CO···D−O contacts as functions of distance and angle.23
method
cocrystal
salt
oxalic acid
reaction
Gavezotti23 Hofmann & Kuleshova24 Hydrogen Hofmann & Kuleshova24 Deuterium Dreiding & Gasteiger25 Overall Dreiding & Gasteiger25 Charge Dreiding & Gasteiger25 H/DBonds
−317.2 −345.3
−249.5 −238.2
−71.0 −106.1
3.3 −1.0
−323.3
−251.6
−88.7
17.0
−303.8 243.0 −105.1
−371.4 −332.2 −74.3
63.2 125.2 −49.4
4.4 −36.0 18.6
Consequently, hydrogen bonds compete with the coulomb interactions. In the case of the deuterated compounds the lowered energy of the zero-point vibration shifts the equilibrium to the left side, favoring product 2 (left side of the equilibrium). By contrast, the analogue experiment with nondeuterated compounds leads to the formation of product 1.
analogue, X = D, the maximum angle and distance are located in the same area, but the low number of determined structures (19) with this type of bond has to be taken into account when comparing both. 4728
DOI: 10.1021/acs.cgd.7b00654 Cryst. Growth Des. 2017, 17, 4726−4729
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(11) Hughes, C. E.; Harris, K. D. M. New J. Chem. 2009, 33, 713− 716. (12) Schwartz, B. J.; Rossky, P. J. J. Chem. Phys. 1996, 105, 6997− 7010. (13) Goncharuk, V. V.; Kavitskaya, A. A.; Romanyukina, I. Y.; Loboda, O. A. Chem. Cent. J. 2013, 7, 103. (14) Delgado, R.; Frausto da Silva, J. J. R.; Amorim, M. T. S.; Cabral, M. F.; Chaves, S.; Costa, J. Anal. Chim. Acta 1991, 245, 271−282. (15) Pant, D.; Levinger, N. E. J. Phys. Chem. B 1999, 103, 7846− 7852. (16) Sasmal, D. K.; Dey, S.; Das, D. K.; Bhattacharyya, K. J. Chem. Phys. 2009, 131, 044509−1-044509-9. (17) Newkome, G. R.; Theriot, K. J.; Fronczek, F. R. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1985, 41, 1642−1644. (18) Newkome, G. R.; Theriot, K. J.; Fronczek, F. R. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1986, 42, 1539−1541. (19) Rajagopal, K.; Krishnakumar, R. V.; Natarajan, S.; Tamilselvi, V. Acta Crystallogr., Sect. E: Struct. Rep. Online 2003, 59, o742−o744. (20) Belabbes, Y.; Lautie, A. Vib. Spectrosc. 1995, 9, 131−137. (21) Crystallographic data of Dox−·Dpy+: C7D7NO4, M = 176,2, T = 172(2) K, triclinic, P1̅, a = 5.672(1) Å, b = 7.615(2) Å, c = 9.503(3), α = 70.04(3)°, β = 88.94(3)°, γ = 71.95(3)°, V = 365.1(1) Å3, Z = 2, ρ = 1.538 Mg m−3 = 0.128 mm−1, F(000) = 176, 2Θmax = 50.0°, 3154 reflections measured, 1183 unique reflections, [R(int) = 0.0416], R1 = 0.0313 with I > 2σ(I), wR2 = 0.0932 for all reflections, GOF = 0.86, CCDC 1457109; cell constants of [Hpy][Hox]: C7H7NO4, triclinic, P1̅, a = 5.64(1) Å, b = 7.90(1) Å, c = 9.66(1), α = 67.7(1)°, β = 87.3(1)°, γ = 71.6(1)°. (22) Crystallographic data of (2) Dox−·Dpy+·2D2O : C7D11NO6, M = 216,2, T = 172(2) K, triclinic, P1̅, a = 5.697(1) Å, b = 7.521(2) Å, c = 11.234(3), α = 97.72(3)°, β = 93.11(3)°, γ = 101.35(3)°, V = 466.1(1) Å3, Z = 2, ρ = 1.541 Mg m−3, = 0.13 mm−1, F(000) = 216, 2Θmax = 50.0°, 5626 reflections measured, 1541 unique reflections, [R(int) = 0.0343], R1 = 0.0274 with I > 2σ(I), wR2 = 0.0679 for all reflections, GOF = 0.934, CCDC 1457110. (23) Mercury tool crystallography package. Gavezzotti, A. Acc. Chem. Res. 1994, 27, 309−314. Gavezzotti, A.; Filippini, G. J. Phys. Chem. 1994, 98 (18), 4831−4837. (24) Hofmann, D. W. M.; Kuleshova, L. N., Eds. FlexCryst Tool Crystallography Package. In Data Mining in Crystallography; Springer, 2009, Vol. 134. (25) Materials Studio Tool Crystallography Package, version 7.0; Accelrys Software Inc., 2013. (26) Cardoso, M.; Carvalho, L.; Sabadini, E. Carbohydr. Res. 2012, 353, 57−61. (27) Scheiner, S.; Cuma, M. J. Am. Chem. Soc. 1996, 118, 1511− 1521.
In conclusion, using the example of pyridine and oxalic acid, we were able to show that the aggregation of molecules in the solid state is highly susceptible to small changes in the nature of the initial molecules. Using D2O as solvent, the inclusion of a neutral molecule in the crystal lattice, forming a cocrystalline salt can be avoided. Therefore, D2O is an effective solvent for targeted control of exchange reactions and correlative crystallization processes.
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EXPERIMENTAL SECTION
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ASSOCIATED CONTENT
(COOH)2·[COO]−[H-NC5H5]+·2H2O 1. A total of 250 mg (1.98 mmol) of oxalic acid·2H2O was dissolved in 157 mg (1.98 mmol) of pyridine and 143 μL of H2O (4 equiv) at 20 °C. The mixture was stirred at 60 °C about 1 h and then cooled to 20 °C. The product crystallized at 30 °C in the form of colorless crystals. [COO]−[D-NC5D5]+·2D2O 2. A total of 250 mg (1.89 mmol) of oxalic acid-d2·2D2O was dissolved in 160 mg (1.89 mmol) of pyridined5 and 138 μL of D2O (4 equiv). The mixture was stirred at 60 °C about 1 h and then cooled to 20 °C. The product crystallized at 45 °C in the form of colorless crystals. S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00654. Additional tables (PDF) Accession Codes
CCDC 1457109−1457110 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*(K.M.) E-mail:
[email protected]. *(D.W.M.H.) E-mail:
[email protected]. ORCID
Klaus Merz: 0000-0001-5287-4525 Notes
The authors declare no competing financial interest.
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REFERENCES
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DOI: 10.1021/acs.cgd.7b00654 Cryst. Growth Des. 2017, 17, 4726−4729
