Communication pubs.acs.org/crystal
Higher-Order Self-Assembly of Benzoic Acid in Solution Weiwei Tang,† Mingtao Zhang,‡ Huaping Mo,§ Junbo Gong,*,† Jingkang Wang,† and Tonglei Li*,‡ †
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, People’s Republic of China ‡ Department of Industrial and Physical Pharmacy and §Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States S Supporting Information *
ABSTRACT: Benzoic acid forms hydrogen-bonded dimers in solution that further stack into tetramers by aromatic interactions. Both dimers and higher-order packing motifs are preserved in the resultant crystal structure. The finding hints at the significance in the hierarchy of intermolecular interactions in driving the self-association process in solution.
P
one crystal structure has been reported as P21/c.22 Seen in Figure 1, the crystal structure consists of a cyclic R22(8) dimer
roduction of organic crystals is of great importance in the science and engineering of materials.1 Understanding and thus control of intermolecular interactions play a crucial role in acquiring solid forms with desired properties.2 While nucleation remains poorly understood, exploration of solution chemistry has shed some light on postulating structural development of solute self-assemblies from prenucleation to crystal packing.3−5 Intermolecularly hydrogen-bonded dimers are mostly found formed between carboxyl groups of solute molecules in certain solvents, and the synthon may be “carried” into the resulting crystals.1 Hydrogen-bonded catemers are also reported formed by 2,6-dihydroxybenzoic acid in chloroform and the synthon is retained in the crystal.6 Other carboxylic acid compounds including acetic acid and tetrolic acid were studied by molecular dynamics and revealed that a variety of hydrogen-bonded associates may concurrently exist in solution.7−9 Another interesting and often debated case is hydrogen-bonded dimer formation of glycine in water.10−12 Higher-order self-assemblies involving multiple types of noncovalent interactions, nonetheless, have rarely been experimentally reported. As any particular self-assembly is a result of competition of the hierarchical intermolecular interactions bestowed by a molecule,13−17 a high-order assembly ought to result from the concerted and compromised tessellation of primary and secondary forces. It is well observed that crystal formation is realized not only by much stronger hydrogen bonds but also by secondary interactions, including π···π, −CH···π, and van der Waals forces.18 It is thereby of great value to identify higher-order selfassemblies in solution that may shed light on the interplay and coordination of various intermolecular interactions through the nucleation process. Herein, we report a study of solution chemistry of benzoic acid (BA) in toluene. Our study discovered the existence of higher-order self-assemblies formed in solution by π···π stacking of hydrogen-bonded dimers. BA is a simple and, yet, characteristic molecule, which bears most traits of molecular interactions commonly encountered in organic crystals. Its crystallization from solution is well-studied;19−21 to date, only © 2017 American Chemical Society
Figure 1. (a) Stacked, hydrogen-bonded dimer motifs in crystal structure of benzoic acid, and (b) 1H NMR proton labeling scheme of the hydrogen-bonded dimer.
synthon and displays a herringbone packing pattern via π···π and −CH···π interactions. Our current study found that the self-assemblies in solution resemble the hydrogen-bonded and π···π stacked motifs in the crystal. BA crystal and toluene solutions of a series of concentrations were first studied by FTIR (Figure 2). In the asymmetric stretching region of CO band, 1800−1620 cm−1 (Figure 2a), there are two major peaks, 1738 and 1694 cm−1, whose intensity ratios are concentration-dependent, indicative of selfassociation most likely by the hydrogen-bonded dimerization through carboxyl groups. The lower frequency band stems from stronger interactions with another solute because toluene is neither a hydrogen-bonding donor nor an acceptor; the other band is of monomeric BA. As the concentration increases, the lower frequency or dimer peak becomes more intensified over the higher frequency or monomer peak. In addition, the dimer peak exhibits slight red shift, from 1694 to 1693 cm−1, when the concentration exceeds 73 mM. In the aromatic stretching Received: August 4, 2017 Revised: September 2, 2017 Published: September 5, 2017 5049
DOI: 10.1021/acs.cgd.7b01078 Cryst. Growth Des. 2017, 17, 5049−5053
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Communication
Figure 2. FTIR spectra of BA crystal and toluene solutions of various concentrations: (a) CO asymmetric stretching region, (b) aromatic −CH deformation region.
region (Figure 2b), concentration-dependent red shift can also be observed. The gradual evolution of the two aromatic −CH deformation bands further suggests that the aromatic ring of the molecule contributes to the solute−solute interaction. At the low concentration, −CH band comprises a doublet, 1097 and 1093 cm−1, likely resulting from two distinct BA species. When the concentration increases, the relative intensity between the two bands is dominated by the higher frequency band. Observation of this band at even higher frequency in the solid-state spectrum confirms that the solution 1097 cm−1 is associated with aromatic intermolecular interactions. The 1093 cm−1 band, which dominates at the low concentration, may stem from aromatic interactions with the solvent, toluene. Intermolecular interactions of BA in solution were further investigated by measuring 1H and 13C chemical shifts. Chemical shift reflects ensemble-averaged interactions in solution but, at the same time, are highly sensitive to subtle changes in the local chemical environment of a molecule. Shown in Figure 3, the carboxyl 13C chemical shift displays a remarkable downfield trend when the concentration increases. The deshielding of 13C resonance implies formation of hydrogen bonding between carboxyl groups, echoing the FTIR finding. The concentrationdependent 13C chemical shift can be well fit to a dimerization isotherm model (Supporting Information; R2 = 0.998; black line in Figure 3a), yielding the dimerization constant of 2064 ± 720 M−1. The ortho-proton (HA) chemical shift bears a similar, concentration-dependent trend; the meta- (HB) and paraprotons (HC), however, display completely different curves, which seem to be composed of two events (Figure 3b). At the low concentration, downfield changes of all protons corroborate the formation of hydrogen-bonded dimers in solution. Deshielding of HB and HC resonances becomes intensified at the high concentration, possibly caused by formation of higherorder oligomers. Accounting for the aromatic interactions between solute molecules that are hinted by the FTIR data, the oligomer species are believed to be stacked hydrogen-bonded dimers as the dimers are significantly dominant over monomeric solute molecules in the solution. The concentration-dependent changes in 1H chemical shift are thereby fit to a combined dimerization and tetramerization isotherm model (Supporting Information). The lines in Figure 3b represent the best fit, which gives the tetramerization constant of about 0.1 M−1. By extrapolating the isotherm model, the changes in chemical shift for the fully bound dimer, relative to
Figure 3. (a) Carboxyl 13C chemical shift and (b) changes in 1H chemical shift of proton HA (black), HB (blue), and HC (green) of BA as a function of concentration in toluene-d8. The black line in (a) represents the best fit to the dimerization isotherm model. The magenta line in (a) and the lines in (b) represent the combined dimerization and tetramerization isotherm model. (c) BA speciation as a function of solute concentration.
the monomer, are derived to be 0.14, 0.07, and 0.05 ppm, respectively, for HA, HB, and HC; for the fully bound tetramer, the corresponding values are 0.08, 0.39, and 0.37 ppm (Table 1). It is evident that the chemical shift of HA is mostly affected by the carboxyl dimerization, and those of HB and HC are mainly dictated by the aromatic interactions formed between hydrogen-bonded dimers. Nonetheless, using the dimerization model alone to perfectly fit the carboxyl 13C resonance does hint at a minimal effect from the subsequent tetramerization 5050
DOI: 10.1021/acs.cgd.7b01078 Cryst. Growth Des. 2017, 17, 5049−5053
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Table 1. Chemically Induced Changes in 1H NMR Chemical Shift by Dimerization and Tetramerization from Dilution Experiments (Δδ) and Theoretical Calculations (Δδcalc.) in Toluene-d8 at 298 K dimerization proton
Δδ
Δδcalc.a
HA HB HC
0.14 0.07 0.05
0.15 0.04 0.02
incorporating various pulse sequences including longitudinal eddy-current delay29 and bipolar PFG pulses.30 A diffusion coefficient can be directly related to the size of the diffusant according to the Stokes−Einstein relationship.27 In our measurement, possible influences by viscosity and temperature were minimized by normalizing detected diffusion coefficients against an internal standard, tetramethylsilane (TMS), which has similar molecular weight and remains monomeric in toluene-d8. The normalized diffusion coefficients were found to decrease nonlinearly when the concentration increased (Figure 4a). The results reveal the size increase of diffusing species
tetramerization Δδ
Δδcalc.a
Δδcalc.b
0.08 0.39 0.37
−0.26 −0.22 −0.66
0.16 0.20 0.37
a
No toluene ring effect considered in calculating chemical shifts. Calculation performed using PD and T heterodimers to mimic the first coordination shell of solvation with the averaged values reported.
b
event on the carbon chemical shift. When the concentrationdependent 13C chemical shifts are also fit to a combined dimerization and tetramerization model (magenta line in Figure 3a), little difference is shown in the dimerization model. The 13 C for the fully bound tetramer, dimer, and monomer are derived by the combined fitting model as 174 ± 2, 173.3 ± 0.1, and 162.9 ± 0.3 ppm, respectively, indicating that the 13C resonance is mostly affected by the dimerization. The fraction of the tetramer population is no more than 6% at the solubility of 690 mM (or 0.104 g per gram of toluene23) (Figure 3c), higher than the amount of the monomer but significantly lower than that of the dimer species. Inclusion of even higher-order aggregates than tetramer was attempted, but fitting could not be converged. Given the low amount of tetramers in solution, any higher-order aggregates seem to be trivial. To further understand how chemical shift is influenced by conformation and self-association, quantum mechanical methods were used to calculate NMR chemical shifts of the hydrogen-bonded dimer and π···π stacked tetramer, as well as possible solvated monomers in toluene. Despite considerably weak interactions between BA and toluene, the phenyl ring of the solvent is expected to cast a significant impact on 1H chemical shifts of the solute. Opposite local magnetic fields are induced by the phenyl current ring when activated by the external magnetic field. By virtue of the liquid structure of toluene,24 the solute likely interacts with toluene by forming parallel displaced (PD) and/or perpendicular T-shape (T) and Y-shape (Y) heterodimer configurations. Different initial configurations of each type of heterodimers were built and optimized, and they were found consistently converging to either PD or T configuration (Figure S1 in SI). Chemical shift calculations of these two heterodimers show close agreement between calculated and experimental changes in chemical shift that result from the carboxyl dimerization and π···π stacking tetramerization processes (Table 1). The calculation thus supports our interpretation of the experimental data and argument of dimer and tetramer formations. Note that without the consideration of the shielding effect by toluene, changes in chemical shift of BA protons because of the tetramerization would show opposite trends from the experimental data. This suggests the importance of considering the toluene solvation as the PD and T heterodimers in calculation of chemical shifts. To explore the dimensions of BA solution species, diffusion coefficients were measured by diffusion-ordered spectroscopy (DOSY) as a function of BA concentration in toluene-d8. Also known as pulsed field-gradient (PFG) techniques,25,26 DOSY measures diffusion coefficient by fitting intensity attenuations of NMR spin echo signals against the strength of pulsed field gradient.27 The methodology is straightforward,28 facilitated by
Figure 4. (a) Diffusion coefficient of BA relative to TMS in toluene-d8 as a function of solute concentration at 298 K. The solid line represents the best fit of the data to a combined dimerization and tetramerization model. The dashed vertical line corresponds to the saturated concentration of BA in toluene. (b) Cylindrical shape model (L-length, D-diameter) used for deriving dimensions of solution species. (c−e) Theoretical dimensions of monomer, dimer, and tetramer species extracted from the crystal structure. Values in the parentheses are the theoretical numbers fitted to the cylindrical model. (f) Averaged length and diameter of BA in toluene-d8 solution derived from the modified Stokes−Einstein equation as a function of solute concentration.
obviously resulting from the self-association. The concentration-dependent trend is fit to the combined dimerization and tetramerization model (SI) using the self-association equilibrium constants, 2064 M−1 and 0.1 M−1, that are determined by the NMR data. The diffusion coefficients of the monomeric, dimeric, and tetrameric species are subsequently derived as 1.99 × 10−9, 1.35 × 10−9, and 0.88 × 10−9 m2/s, respectively. Assuming the respective species to be spherical in shape, the hydrodynamic radii are estimated as 2.03, 3.00, and 4.60 Å, according to the Stokes−Einstein equation. The diffusion coefficients can be further fit to a cylindrical shape model31,32(Figure 4b), leading to dimensions of 7.8 × 4.5, 15.5 × 4.1, and 18.6 × 5.8 Å for the monomer, dimer, and tetramer, respectively, matching those motifs in the crystal structure (Figure 4c−e). Note that the dimension estimate is based on converting the spherical shape, which is used in the Stokes− Einstein equation, to a cylinder model. Such conversion suffers from larger errors when the diffusant has a larger aspect ratio. Because the measured diffusion coefficient is averaged mainly over the three species, the averaged long and short dimensions are plotted as a function of concentration based on the dimerization and tetramerization model (Figure 4f). The short dimension or diameter of BA species seems to remain constant and the length increases significantly, indicating the formation 5051
DOI: 10.1021/acs.cgd.7b01078 Cryst. Growth Des. 2017, 17, 5049−5053
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Fukui function, f−, can be found around the phenyl ring (Figure 5c). Matching of these spots corroborates with the π···π stacking by the dimers.18 Because Fukui function is associated with local softness, matching of Fukui functions characterizes the soft−soft type of interactions including aromatic stacking.18,33 The stacking energy between the dimers is found to be significant, −51.3 kJ/mol (two π···π contacts), smaller than but comparable to the hydrogen-bonding energy. The local electronic properties support that the hydrogen bonding is the primary force for the intermolecular interaction, and the π···π stacking is the secondary. Jointly, these interactions determine how the solute molecules self-associate in the solution, as well as in the crystal. In summary, BA molecules were found in toluene to selfassociate extensively by forming hydrogen-bonded dimers. As the concentration increases, there are a few percent of the dimers that can further assemble into π···π stacked tetramers. The association constant of the tetramer formation is much lower than that of the dimerization, indicating that the π···π association is considerably weaker than the hydrogen bonding. This conclusion is supported by the energy calculation that found that the aromatic energy is weaker by about 7.5 kJ·mol−1 (per interaction) than the hydrogen bonding. The importance of the higher-order self-association is illustrated in the structural similarities between the solution species and the packing motifs found in the crystal structure. Both the hydrogen-bonded dimer and the tetramer are present in the solution and “carried” into the crystal. While the mechanism of nucleation may be kinetically regarded as a second-order phase transition, the structural progression could be a continuous process of selfassembling. Packing of solute molecules starts well below the saturation and self-assembled aggregates become further arranged into nuclei, likely maintaining their interacting preferences that are dictated by the hierarchy of intermolecular interactions. In the case of BA, the primary force or hydrogen bonding leads to self-associated dimers, which further form higher-order associates by secondary forces. Possibly, the selfassemblies keep growing and revolving in the nuclei, but the structural motifs sustained by the primary and secondary forces will likely survive.
of hydrogen-bonded dimers. At the high concentration, the diameter displays a remarkable increase while the length increases slightly, reflecting the formation of the π···π stacking of hydrogen-bonded dimers. Local electronic structures of the molecule were analyzed in order to understand the origin of intermolecular interactions that are responsible for the self-assembly in solution and in the crystal. Our previous studies demonstrated using local hardness and softness to characterize the locality and regioselectivity of intermolecular interactions with regard to molecular packing.18,33 Electrostatic potential (ESP) and Fukui functions of single BA molecule were derived and visualized (Figure 5).
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b01078. Experimental and computational section, BA−toluene heterodimer configurations, fitting models (PDF)
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Figure 5. (a) Electrostatic potentials mapped on van der Waals surface of two benzoic acid molecules. (b) Hydrogen-bonded dimer motif. (c) Nucleophilic Fukui function, f+, (top right and bottom left) and electrophilic Fukui function, f−, (top left and bottom right) mapped on the van der Waals surface. Match between f+ and f− as found in optimized and crystal structures are marked by black arrows. (d) Tetramer motif. The isovalue of 0.001 au is applied for van der Waals surface.
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Junbo Gong: 0000-0002-3376-3296 Tonglei Li: 0000-0003-2491-0263 Notes
Larger spots of either positive or negative ESP are found around the carboxyl group, contributing to the hydrogen bonding of the cyclic dimer (Figure 5b; −66.5 kJ/mol of two hydrogen bonds). Electrostatic interaction is generally regarded as a major component of hydrogen bonding.34,35 In addition, large spots of nucleophilic Fukui function, f+, and electrophilic
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS W.W. acknowledges funding support from the China Scholarship Council (CSC), and J.B. thanks the National Natural 5052
DOI: 10.1021/acs.cgd.7b01078 Cryst. Growth Des. 2017, 17, 5049−5053
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Science Foundation of China (NSFC; No. 21676179 and No. 91634117) for financially supporting the research. T.L. thanks Chao Endowment for supporting the research.
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