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Deuterium shifts the equilibrium: How heavy water can influence organic multicomponent crystal formation Dennis D. Enkelmann, Detlef W. M. Hofmann, and Klaus Merz Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00654 • Publication Date (Web): 17 Jul 2017 Downloaded from http://pubs.acs.org on July 18, 2017
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Crystal Growth & Design
Deuterium shifts the equilibrium: How heavy water can influence organic multicomponent crystal formation †
*‡
Dennis D. Enkelmann , Detlef W.M. Hofmann , Klaus Merz
*†
†
Inorganic Chemistry I, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany
‡
CRS4, Loc. Piscina Manna 1, 09010 Pula (CA), Italy
Supporting Information Placeholder 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 H/Dexchange.
The role of deuterium in molecular evolution and in chem1 ical processes has increased in the recent years. Substitution of H2O by D2O is generally not seen as an influencing parameter in relation to reaction thermodynamics and product 2,3 formation. 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 BornOppenheimer 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 non-deuterated com4-7 pounds. Instead even the comparison of H2O and D2O reveals alternations in strength and number of existing hy9 drogen bonds. This leads to deviations of melting and boiling points and the temperature of maximum density (D2O 10
11,22º C und H2O 4,08º C).
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.
can be used for targeted control of reaction processes. Condi12,13 tioned by the higher self-aggregation and the lower dissociation constant of D2O, weak acids show a lower pKa value 14 in heavy water than in non-deuterated water. 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-ß-cyclodextrin by Sasmal et al. revealed a reduction in solvation velocity of 25% in D2Osolution, comparable to insights into solvation dynamics of 15, 16 nanoscale ZrO2-particles in D2O-solution. 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. Solvent H2O
2 (COOH)2 2 H2O +
(HC2O4)-
N - 2 H2O
Solvent D2O
(COOD)2 2 D2O +
N H
2 H2O
N D
2 D2O
(COOH)2
D5 N
(DC2O4)-
Up to now, crystalline pyridinium oxalate and pyridinium + hydrogen oxalate ([Hpy ] ∙ [Hox ]) compounds have been obtained as cocrystalline salts together with oxalic acid 17-19 (H2ox) from solution. For example, the cocrystalline salt + . . hydrate H2ox Hox Hpy . 2H2O (1) was synthesized by crystallizing oxalic acid dihydrate from a water/pyridine 19 mixture in the presence of L-Proline.
Hughes and Harris showed that substitution of water by heavy water can influence the formation of polymorphic 11 modifications of the amino acid glycine. However, the impact of heavy water is not limited to the formation of isotopic polymorphs. Due to its deviating properties from H2O, D2O
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+ Figure 1: Molecular arrangement of 1 H2ox.Hox .Hpy .2H2O in the solid state 19 and scheme .
py
py
H
H
+ Figure 2: Molecular arrangement of (2) Dox . Dpy . 2D2O in the solid state and scheme.
H2ox ----- Hox ----- H2ox -----Hox
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.
H2ox = (COOH)2 Hox- = HOOC-COO= H2 O
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 20 spectroscopic methods. 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 acidd2 ∙ 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 charac+ terized as the salt Hox . Hpy . The analogous reaction using deuterated starting materials leads to an isostructural salt of + 21 the composition Dox . Dpy . 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 + 22 and consists of Dox . Dpy . 2D2O.
Compound 1 aggregates via strong hydrogen bonds between hydrogen-oxalate, oxalic acid and water molecules in a zig-zag 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. 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 zig zag 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.
(1)
(2)
- ⋅ + ⋅ ⇌ ⋅ - ⋅ + ⋅
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 26 the solvent. 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.
2
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To understand the competitive reactions the molecule-pair 23 interactions in the solid state have been analyzed (Table 1).
C=O…H-O
It is conspicuous that the energetically dominating interaction [Dox …Dox ] in 2 is also present in the non-deuterated structure of 1. However, in 1 it is insignificant compared to the other interactions (rank 12). ⋅ - ⋅ + ⋅ Rank
Interation
1
- ⋯ +
2 3 4 5 6 7 12 18 >20
⋯ 2 H2ox ⋯ 2 -
H2ox ⋯ 2 H2O⋯H2O
Energy -28,0 -27,7
- ⋅ + ⋅
Rank
Interation
2
- ⋯ +
3
-27,3 5
+ ⋯ + -13,3
11
- ⋯ -
-8,8
1
-5,9
4
>-5,7
6
2 ⋯ -
⋯ 2 H2O⋯H2O -
-22,8 -21,8
---
-23,1 -18,4
⋯ 2 ---
Energy
D2O⋯D2O
+ ⋯ +
-16,4 -8,4
C=O…D-O
---
-10,8
- ⋯ - ⋯ 2 D2O⋯D2O
-24,7 -17,3 -15,4
Table 1: Calculated intermolecular potentials of the dominating intermolecular potentials in the crystal structures of 1 and 2 (hydrogens normalized). UNI force field calculations23 Xpy+=Pyridinium, Xox-=hydrogen oxalate, X2ox= oxalic acid.
The difference between interactions of deuterated and non-deuterated 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…O=C], [O-X…O=C] and [ >O…X-O]. In Figure 3, the frequency of the interaction [C=O…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 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.
Figure 3: Frequency of C=O···H-O contacts compared to frequency of C=O···D-O contacts as functions of distance and angle.23
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 mechanis5 tic approach. A general discussion can be found at Scheiner 27 and Cuma. Under estimation of a harmonic potential the zero-point vibrational energy is correlated to the mass as follows: #$
% ) ( 4π μ
Whereby k is the spring constant and µ the reduced mass.
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A third possibility is the analysis with force fields. We investigated the energy of formation with three different force fields. The first method included the calculation of formation energies with effective Lennard-Jones potentials, which did not 23 reveal any difference between hydrogen and deuterium. The positive formation energy could be interpreted as the reason for a slight, thermodynamically driven tendency towards decomposition of 1. The very low formation energy portends the influence of external effects like H/Dsubstitution. The second method is based on a force field derived from 24 the CSD using data mining. 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 /0 /0 by heavy water (∆, $ 17 >0 ). 123
123
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 towards formation of /0 cocrystalline salt 1 (the right side) (−36 , whereas hydro123 gen bonds shift the equilibrium towards compound 2 (left /0 . side) (18.5 Method
123
Cocrystal
Salt
Gavezotti23
-317,2
-249,5
Oxalic acid -71,0
Reaction 3,3
Hofmann &Kuleshova24 Hydrogen
-345,3
-238,2
-106,1
-1,0
Hofmann &Kuleshova24 Deuterium
-323,3
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EXPERIMENTAL SECTION -
(COOH)2 . [COO] [H-NC5H5] . 2 H2O 1 250 mg (1.98 mmol) of oxalic acid ∙ 2H2O were dissolved in 157 mg (1.98 mmol) of pyridine and 143 μl and H2O (4 eq.) at 20° C. The mixture was stirred at 60 ° C about one hour and then cooled to 20 ° C. The product crystallized at 30 ° C in the form of colorless crystals. -
[COO] [D-NC5H5] . 2 D2O 2 250 mg (1.89 mmol) of d2-oxalic acid ∙ 2D2O were dissolved in 160 mg (1.89 mmol) of d5-pyridine and 138 µL and D2O (4 eq.) The mixture was stirred at 60 ° C about one hour and then cooled to 20 ° C. The product crystallized at 45 ° C in the form of colorless crystals.
ASSOCIATED CONTENT Supporting Information: CIF-files giving X-ray data with details of refinement procedures for [COO] [D-NC5H5] and [COO] [D-NC5H5] . 2D2O; CCDC Nr. 1457109, 1457110 are available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION -251,6
-88,7
17,0
Corresponding Author †
Dreiding &Gasteiger25 Overall
-303,8
-371,4
63,2
4,4
Dreiding &Gasteiger25 Charge
243,0
-332,2
125,2
-36,0
Dreiding &Gasteiger25 H/D-Bonds
-105,1
-74,3
-49,4
18,6
Dr. Klaus Merz, E-Mail:
[email protected] ‡
Dr. Detlef W. M. Hofmann, E-Mail:
[email protected] Present Addresses †
Inorganic Chemistry I, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany ‡
Table 2: Calculations of the formation energies of cocrystalline salt 1 from 2 and /0 oxalic acid (unit: ).
CRS4, Loc. Piscina Manna 1, 09010 Pula (CA), Italy
Notes The authors declare no competing financial interests.
123
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. 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.
REFERENCES [1] L. G. Pedersen, L. Bartolotti, L. Li, Journal of Theoretical Biology, 2006, 238, 914–918. [2] J. D. Dunitz, R. M. Ibberson, Angew. Chem. Int. Ed., 2008, 47, 4208–4210. [3] T. Matsuo, A. Inaba, O. Yamamuro, N. Onoda-Yamamuro, J.Phys.: Condens. Matter, 2000, 12, 8595–8606. [4] a. K. Merz, A. Kupka, Crystal Growth & Design, 2015, 15, 1553-1558. b. A. R. Ubbelohde, K. J. Gallagher, Acta Crystallographica, 1955, 871– 83. [5] A. Kupka, V. Vasylyeva, D. W. M. Hofmann, K. V. Yusenko, K. Merz, Cryst. Growth Des., 2012, 12, 5966-5971. [6] V. Vasylyeva, T. Kedziorski, N. Metzler-Nolte, C. Schauerte, K. Merz, Cryst. Growth Des., 2010, 1, 4224-4226. [7] S. Crawford, M. T. Kirchner, D. Bläser, R. Boese, W. I. F. David, A. Dawson, A. Gehrke, R. M. Ibberson, W. G. Marshall, S. Parsons, O. Yamamuro, Angew. Chem., 2009, 121, 769–771.
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[8] K. Roettger, A. Endriss, J. Ihringer, J. Acta Crystallogr. Sect. B: Struct. Sci., 1994, B50, 644-648. [9] K. Winkel, M. Bauer, E. Mayer, M. Seidl, M. S. Elsaesser, T. Loerting, J. Phys.: Condens. Matter, 2008, 20, 494212/494211494212/494216. [10] E. Swift, J. Am. Chem. Soc., 1939, 61, 1293-1294. [11] C. E. Hughes, K. D. M. Harris, New J. Chem., 2009, 33, 713-716. [12] B. J. Schwartz, P. J. Rossky, J. Chem. Phys., 1996, 105, 6997-7010. [13] V. V. Goncharuk, A. A. Kavitskaya, I. Y. Romanyukina, O. A. Loboda, Chemistry Central Journal, 2013, 7, 103. [14] R. Delgado, J. J. R. Frausto da Silva, M. T. S. Amorim, M. F. Cabral, S. Chaves, J. Costa, Analytica Chimcia Acta, 1991, 245, 271-282 [15] D. Pant , N. E. Levinger, Phys. Chem. B, 1999, 103, 7846-7852. [16] D. K. Sasmal, S. Dey, D. K. Das, K. Bhattacharyya, J. Chem. Phys., 2009, 131, 044509-1 - 044509-9. [17] G. R. Newkome, K. J. Theriot, F. R. Fronczek, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1985, 41, 1642-1644. [18] G. R. Newkome, K. J. Theriot, F. R. Fronczek, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1986, 42, 1539-1541. [19] K. Rajagopal, R. V. Krishnakumar, S. Natarajan, Acta Crystallogr., Sect. E: Struct. Rep. Online, 2003, 59, o742-o744. [20] Y. Belabbes, A. Laurie, Vibrational Spectrosc., 1995, 9, 131-137. [21] Crystallographic data of Dox - . Dpy +: C7D7NO4, M=176,2, T=172(2) K, triclinic, P-1, a= 5.672(1) Å, b=7.615(2) Å, c=9.503(3), α=70.04(3)o, β=88.94(3)o, γ=71.95(3)o, V=365.1(1) Å3, Z=2, ρ=1.538 Mg m-3 = 0.128 mm-1, F(000)=176, 2Θmax=50.0o, 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, P-1, a= 5.64(1) Å, b=7.90(1) Å, c=9.66(1), α=67.7(1)o, β=87.3(1)o, γ=71.6(1)o, [22] Crystallographic data of (2) Dox- . Dpy+ . 2D2O : C7D11NO6, M=216,2, T=172(2) K, triclinic, P-1, a= 5.697(1) Å, b=7.521(2) Å, c=11.234(3), α=97.72(3)o, β=93.11(3)o, γ=101.35(3)o, V=466.1(1) Å3, Z=2, ρ=1.541 Mg m-3, = 0.13 mm-1, F(000)=216, 2Θmax=50.0o, 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; A. Gavezzotti, Acc. Chem. Res. 1994, 27, 309-314; A. Gavezzotti, G. Filippini, J. Phys. Chem., 1994, 98 (18), 4831-4837. [24] D. W. M. Hofmann, L. N. Kuleshova, FlexCryst tool crystallography package; eds. Data mining in crystallography, Springer, 2009, Vol. 134. [25] Materials Studio tool crystallography package, Accelrys Software Inc., 2013, version 7.0 [26] M. Cardoso, L. Carvalho, E. Sabadini., Carbohydrate research, 2012, 353, 57-61. [27] S. Scheiner, M. Cuma, J. Am. Chem. Soc., 1996, 118.6, 1511-1521.
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For Table of Contents Use Only Deuterium shifts the equilibrium: How heavy water can influence organic multicomponent crystal formation *
Dennis D. Enkelmann , Detlef W.M. Hofmann , Klaus Merz
*
Heavy water allows the control of reaction pathways, in this case an acid-base reaction. D2O can be used in a targeted manner to synthesize an alternative crystalline reaction product.
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