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Catalytic Effect of Solvent Vapors on the Spontaneous Formation of Caffeine-Malonic Acid Co-Crystal Canran Ji, Mikaila C Hoffman, and Manish A. Mehta Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01164 • Publication Date (Web): 08 Mar 2017 Downloaded from http://pubs.acs.org on March 11, 2017
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Catalytic Effect of Solvent Vapors on the Spontaneous Formation of Caffeine-Malonic Acid Co-Crystal Canran Ji,‡ Mikaila C. Hoffman,‡ and Manish A. Mehta* Department of Chemistry and Biochemistry, Oberlin College, 119 Woodland Street, Oberlin, Ohio 44074, United States KEYWORDS: Caffeine, malonic acid, vapor digestion, solid-gas, catalysis. Supporting Information Placeholder ABSTRACT: Caffeine (a model pharmaceutical mimic) and malonic acid (a common excipient partner) are known to form a
molecular co-crystal spontaneously over about 1 week when their powders are mixed at ambient conditions. We report the dramatic catalytic acceleration of this reaction when the mixture of powders is exposed to vapors of common laboratory solvents. Acetone and methanol vapors show rate enhancements over 1000-fold, effecting quantitative conversion in less than 5 minutes. The reaction progress was tracked ex situ by powder X-ray diffraction and products verified by 13C solid-state NMR. Our data show no evidence of an intermediate phase. Gravimetric experiments show that solvent vapor uptake is not stoichiometric and is reversible. This rare example of gas phase catalysis of supramolecular transformations has important implications for a deeper mechanistic understanding of diffusion controlled solid-solid reactions.
Molecular co-crystals have enjoyed fresh attention for their promise as pharmaceutical agents and novel materials.1 The two standard methods for their synthesis are either solvent evaporation or mechanochemistry.2-5 The latter is valued as a green alternative to traditional solvent-based methods for synthesizing solids.6-8 The guile and simplicity of mechanochemistry are matched only by the mystery of its mechanism.9 In a related class of transformations, a few systems are known to form co-crystals spontaneously, by simply mixing the reactant powders – a synthesis requiring no energy input.10-13 One such system is the 2:1 co-crystal of caffeine and malonic acid, where a model active pharmaceutical ingredient (API, caffeine, CA) combines with an excipient coformer (malonic acid, MA).10 This system has been the subject of several recent studies.14,15 Here, we report the unexpectedly dramatic catalytic effect of organic solvent vapors on the spontaneous formation of this co-crystal. (a)
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Figure 1. Experimental powder X-ray diffraction (PXRD) traces of (a) caffeine, (b) malonic acid, and (d) the 2:1 co-crystal produced by neat grinding (ball milling). The PXRD trace calculated from the co-crystal structure is given in (c). PXRD trace of co-crystal pro-
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duced by acetone vapor exposure for 4 minutes is given in (e) and co-crystal formed by exposure to ethanol vapor for 10.5 minutes in (f). Both (e) and (f) show quantitative conversion to co-crystal.
The effects of organic vapor digestion have been reported in other systems, though mostly for solid-state reactions involving covalent bond chemistry.16-18 As such, this falls into a larger class of gas-solid reactions, which have a rich history.19-22 Reports of the catalytic effect of a vapor phase on purely solid-solid reactions, however, are rare.23-25 Within the realm of supramolecular chemistry, this occurrence is even more unusual.26,27 Ultimately, these are diffusion-controlled reactions in heterogeneous environments. It has been reported that exposure to high aqueous humidity tends to accelerate spontaneous co-crystal formation, although it is likely that the mechanism we report here may be different from that based on aqueous vapor.28,29 To test the possibility that solvents other than water may have a similar effect, we exposed a mixture of CA and MA powders to organic solvent vapors. Caffeine and malonic acid were ground and sieved separately to isolate the 45-75 µm grain size fraction. The 2:1 stoichiometric mixture of CA and MA was first gently mixed by vortexing. Borrowing a technique used to mix dry ingredients in baking, we then triple-sifted the powder mixture using a set of coarse sieves to assure maximum mixing (grain-to-grain contact) without any mechanical crushing or grinding. The reacting powder mixture was then packed in a PXRD sample holder and the holder placed in a sealed solvent vapor chamber. (Details are given in the Supporting Information.) On exposure to acetone vapor, the conversion to co-crystal is quantitative in less than 5 minutes (Figure 1e). On similar exposure to ethanol vapors, conversion is complete in less than 11 minutes (Figure 1f). To our surprise, the vapors of many common solvents led to an acceleration in the spontaneous formation of CA:MA co-crystal (see below). (a)
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Figure 2. Solid-state 13C CP-MAS NMR spectra of 2:1 caffeine:malonic acid co-crystal made by (a) neat grinding (ball milling); (b) exposure to acetone vapor; (c) exposure to ethanol vapor. Each spectrum is at natural abundance, 30 kHz MAS and 150.987 MHz (13C), externally referenced to neat TMS. At this spin speed, the spectrum contains no spinning side bands.
Since PXRD detects only phases that diffract, we sought an independent spectroscopic verification that the co-crystal formed by vapor digestion is the same as that produced by neat grinding. The solid-state 13C magic angle spinning (MAS) NMR spectrum of co-crystal generated by neat grinding is shown in Figure 2a. Spectra of co-crystal produced by acetone vapor (Figure 2b) and ethanol vapor (Figure 2c) exposure are indistinguishable from the spectrum of co-crystal generated by neat grinding, as reflected by the chemical shifts and line widths of all ten 13C resonances. At this level of dispersion, the spectra show no additional resonances of a crystalline polymorphic or amorphous phase, nor are there signals from reactant residue. Vapor digestion produces co-crystal that is phase pure. (Details are given in the Supporting Information.) It is technically challenging to perform spectroscopic measurements in situ during organic vapor digestion,27 though some important advances have recently been reported.30-32 Thus, we resorted to ex situ analyses of the reacting powders subjected to organic vapors. We exposed a series of samples to successively longer times in acetone vapor, placed each sample in high vacuum for 3 minutes to remove adsorbed vapors, and collected their PXRD patterns. Figure 3 shows that there is rapid, steady conversion to co-crystal, as indicated by the diffraction signatures. Noticeable co-crystal product is present after 30 seconds of exposure, and by 4 minutes the reaction is nearly complete. The data do not show any evidence of an intermediate diffracting phase.
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Figure 3. PXRD patterns of the reaction mixture sampled (ex situ) at increasing exposure times to acetone vapors. The bottom panel is the powder pattern of the co-crystal made by neat grinding, shown for reference. Arrows in the top panel point to reflections of cocrystal product and the input reactants used to track reaction progress. The 10-30 degree signature region of 2θ is shown.
We performed similar experiments using other, common laboratory solvents and observed catalytic acceleration for conversion to co-crystal for many of them. The results are summarized in Table 1. Data do not show any clear correlations between the reaction time and the protic or aprotic nature of the solvent, nor do the data show any connection with the solvent vapor pressure, dipole moment, or dielectric constant. The fastest of the vapor catalysts, acetone and methanol, exhibit a rate enhancement of over 1000-fold compared with spontaneous formation at ambient conditions (5 minutes versus seven days). We do not expect hydrocarbon solvents to interact strongly with the reactants, which is consistent with no observed catalytic effect for n-pentane. The reacting powder is seen to become deliquescent in isopropanol vapor, continuously gaining in mass and becoming wet with solvent. It is difficult to make quantitative statements about the nature of interaction between solvent vapors and reacting powders. To quantitate the interaction between the reacting powder and solvent vapor, we performed in situ gravimetric experiments to track mass change in the reacting powders when exposed to solvent vapors. The data are shown for acetone and ethanol exposure in Figure 4. We observe that the mass of the reacting powders increases by a non-stoichiometric amount, reaching a maximum of a few percent. Furthermore, when the source of solvent vapors is removed, the vapors outgas and the mass of the mixed powders is restored to its initial value. This illustrates a key result that the mass uptake due to solvent vapors is reversible. Table 1. Reaction times for the different solvents studied. Also given are the vapor pressure, dipole moment, and dielectric constant of solvents used for the experiments at 25 °C.33
Solvent Acetone Methanol Ethanol THF Acetonitrile Diethyl Ether Ethyl Acetate Isopropanol n-Pentane
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2.88 1.70 1.69 1.75 3.92 1.15 1.78 1.58 0
20.7 33.0 25.3 7.52 36.6 4.27 6.08 18.3 1.84
Deliquescent No Effect
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Figure 4. Mass gain as percent of mass of reacting powders when exposed to (a) acetone and (b) ethanol vapor. The mass was recorded every 10 seconds by a data logger. At the cusp point the vapor sources were removed from the balance chamber while the data logging continued. The mass is seen to return to its original value.
To further investigate the catalytic effect, we performed a series of start-stop experiments by exposing a mixture of reacting powders to the vapors of one solvent, to achieve partial conversion, then exposing the same sample to another solvent’s vapors. In all instances, the samples were placed in vacuum for 3 minutes after each exposure to remove adsorbed vapors and arrest their catalytic action. Figure 5 shows data for samples exposed to acetone and ethanol vapors in serial succession. In Figure 5a we see nearly complete conversion to co-crystal after 5 minutes in acetone vapor, and the conversion is complete after 10 additional minutes in ethanol vapor (Figure 5b). Initial exposure to ethanol vapors for 5 minutes effects less conversion (Figure 5c), although 10 additional minutes in acetone vapor leads to complete conversion (Figure 5d). Other, similar experiments show that the catalytic conversion to co-crystal may be initiated with one solvent’s vapors, stopped by exposure to vacuum, and resumed with the vapors of another solvent. These experiments, combined with earlier spectroscopic data, seem to indicate that the catalytic modification of the reaction path is largely independent of the solvent identity. (a)
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Figure 5. PXRD patterns of reacting powders exposed to vapors of two different solvents. Trace (a) is after 5 minutes of exposure to acetone, followed by 10 additional minutes of exposure to ethanol (b). Trace (c) is after 5 minutes in ethanol vapor, followed by 10 additional minutes in acetone (d) vapor. Samples were subjected to 3 minutes of vacuum after each exposure.
Based on reported results at elevated humidity, we suspect the surface area of the reacting grains plays an important role.29 For the experiments presented up to this point, the 45-75 µm fraction was used for all powders. Repeating the vapor digestion experiments using a larger grain size fraction (75-106 µm) shows that the rate enhancement depends on the size of the reacting grains. Data in Figure 6 shows that larger grains react more slowly in the presence of acetone and ethanol vapors. Further experiments across grain sizes, as reported by Rastogi et al., are likely to reveal more about the details of the diffusion process across gain boundaries.19,20
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Figure 6. PXRD patterns of reacting powders made up of 45-75 µm (a, c) and 75-106 µm (b, d) size fractions exposed to vapors of acetone (a,b; 4 minutes) and ethanol (c, d; 11 minutes) vapors. The larger particle size fractions show incomplete conversion compared with the smaller particles.
We report the catalytic effect of solvent vapors on the spontaneous formation of caffeine-malonic acid co-crystal. The effect we observe is robust and finite for many common laboratory solvent vapors. The behavior exhibited by this one co-crystal could have important implications for thermodynamically driven self-assembly of supramolecular systems. It also raises deeper questions about reaction kinetics in diffusion controlled solid-solid reactions. For example, what is the nature of molecular interaction between solvent and reactants that is responsible for catalytic action? As the reaction proceeds, one set of supramolecular synthons gives way to another. It is natural to ask if there are transient synthons between solvent and reactants. Lessons from gas phase microsolvation may be applicable.34 For the molecules to mix – ultimately to combine stoichiometrically at the unit cell level – there must be transport. The nature of that transport in the solid state, which is certain to be anisotropic and driven by chemical potential, is poorly understood at best. A single-crystal-to-single-crystal experiment, wherein the reactants are brought into contact at specific crystal faces, and the spontaneous co-crystal formation tracked using real-time optical or X-ray diffraction techniques, may shed light on the nature of the diffusive transport. The phenomenon reported here also underscores the importance of thermodynamic measurements of co-crystal systems. The literature is embarrassingly short on quantities such as enthalpies of formation, heat capacities, and standard molar entropies of co-crystals.35 Vapor digestion is an alternate green route to traditional solvent-based synthetic methods for solids. Gas-phase catalysts hold promise for solid-solid reactions driven by chemical potential, requiring very low energy input. Most reports of vapor digestion to date concern covalent bond chemistry, where the energies are greater in magnitude. It is ironic and surprising that such effects have not been more widely seen for non-covalent transformations, where the interactions are subtler. Preliminary work in our laboratory on other co-crystal systems indicates that the catalytic effect of organic solvent vapors may be more widespread. ASSOCIATED CONTENT Supporting Information. Details of sample preparation, vapor digestion experiments, time sampled data for exposure to ethanol vapor, effectiveness of vacuum stopping, powder X-ray diffraction, NMR experiments, gravimetric experiments. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected] Author Contributions
‡These authors contributed equally. Notes The authors declare no competing financial interest.
A CKNOWLEDGMENT We thank Melinda Keller and William Mohler (Oberlin College) for their assistance with the gravimetric experiments. This work was supported by NSF RUI grant CHE-1464948, NSF-MRI grant DMR-0922588 for the acquisition of a powder X-ray diffractometer, and a Henry Dreyfus Teacher-Scholar grant (MAM) from the Camille and Henry Dreyfus Foundation.
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For Table of Contents Use Only Manuscript title:
Catalytic Effect of Solvent Vapors on the Spontaneous Formation of Caffeine-Malonic Acid Co-Crystal
Authors:
Canran Ji, Mikaila C. Hoffman, and Manish A. Mehta
TOC Graphic:
Solvent Vapors 5 minutes
Synopsis: We report the catalytic acceleration for the spontaneous formation of caffeine-malonic acid co-crystal by exposure to a variety of common laboratory solvent vapors, with rate enhancements over 1000-fold. Temporal gravimetric data show that solvent vapor uptake is not stoichiometric and is fully reversible. Data also show that larger grains react more slowly.
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