Mechanism of Contact-Induced Heterogeneous Nucleation - Crystal

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Mechanism of Contact-Induced Heterogeneous Nucleation Yuqing Cui,† Jelena Stojakovic,† Hideomi Kijima,†,‡ and Allan S. Myerson*,† †

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ‡ Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan S Supporting Information *

ABSTRACT: Understanding and controlling nucleation is a longstanding issue in the field of crystallization and solid state chemistry. Herein, we use gold−thiol self-assembled monolayers (SAMs) as heterosurfaces in combination with contact force to induce nucleation. Our approach elucidates the mechanism of contactinduced heterogeneous nucleation and has clear technological implications in that it reduces induction time and controls polymorphism of pharmaceutical crystals. The combination of SAMs and contact force can immediately induce nucleation under conditions that do not otherwise promote fast crystallization. The chance of nucleation is enhanced by SAMs that interact strongly with solute molecules. These observations and analyses of obtained crystals led us to conclude that contact-induced heterogeneous nucleation follows a similar path as undisturbed heterogeneous nucleation in the early stage, but departs from it at the later stage due to the interruption by contact force. In contrast to undisturbed heterogeneous nucleation, crystals are not attached to and do not chemically interact with SAMs in contact-induced heterogeneous nucleation.

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INTRODUCTION Heterogeneous nucleation has been widely used for enhancing nucleation and growth kinetics,1−4 controlling polymorphs,5−12 and probing nucleation mechanisms.13−15 This study investigates the mechanism of contact-induced heterogeneous nucleation. Nucleation of new phases has remained one of the most enigmatic processes in nature despite the fact that it has long been studied.16 Indeed, observations and studies of nucleation mechanism on a molecular scale have been challenging. Many theories on nucleation have emerged in the past including the classical nucleation theory,17,18 the two-step nucleation theory,19 and the dense liquid theory.20 Many studies of nucleation mechanisms employ templated heterogeneous nucleation because the templates can be designed and tailored to the needs of the studies. For example, Pouget et al.14 used a stearic acid monolayer as a template to stabilize and locate prenucleation clusters for cryo-transmission electron microscopy (TEM) imaging. Harano et al.13 took advantage of an aggregated particle of carbon nanohorns bearing amine groups as templates to study the mechanism of heterogeneous nucleation with single-molecule real-time transmission electron microscopy. Diao et al.21 probed the mechanism of the formation of solute molecular clusters based on nucleation events induced by templates of nanopores of various shapes. Kulkarni et al.22 explored the interactions of solute molecules and foreign surfaces in heterogeneous nucleation by using selfassembled monolayers (SAMs). Even in contact secondary nucleation, we have previously advanced the understanding of © XXXX American Chemical Society

its mechanism through the proper choice of parent crystals of a certain polymorph, which is another form of templating.23 In this study, SAMs are used as the heterogeneous template surfaces. It is demonstrated that contact-induced heterogeneous nucleation is similar to undisturbed heterogeneous nucleation in that solute molecules are stabilized and organized by the heterosurface, but the mechanisms of the two are also fundamentally different in that crystals formed due to contact are not bonded to the template, which is the opposite to what was observed of undisturbed nucleation on SAMs in previous studies.5,22 We proposed a mechanism for contact-induced heterogeneous nucleation to explain these observations. We also argue that in the context of contact secondary nucleation, functional groups alone are capable of attracting, stabilizing, and arranging solute molecules, which results in nucleation upon contact. Heterogeneous nucleation has also been used to achieve the control of crystal polymorphism with the heterosurface templates ranging from crystalline substrates, 11,24,25 SAMs,5−7,26 insoluble polymer surfaces,27 and microgels.28 The control of polymorphism is mostly achieved through chemical reactions,6,22,29 lattice matching (epitaxy),5,11 and dipole moments5 between solute molecules and reactive surfaces. These works all relied on an undisturbed heterogeneous nucleation mechanism. The induction time of these systems can be long and unpredictable, and thus render it Received: August 29, 2016

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DOI: 10.1021/acs.cgd.6b01284 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Table 1. Summary of Experimental Characterization by Contact Angle and IR of Gold, and SAMs of 4MP, MHDA, and 4MBP SAM contact angle ±3.0° characteristic IR peak cm−1 (bulk) and assignment

gold

4MP

MHDA

4MBP

79 N/A

64 1467 (1476) C−N stretch aromatic amines

46 2854 (2848) alkane C−H stretch

84 1472 (1476) C−C stretch (in-ring) aromatics

solution was heated up to 60 °C. The solution was then filtered (0.2 μm pore size) and transferred into a prewarmed glass Petri dish in which a SAM or unfunctionalized gold substrate was already placed. The Petri dish was then sealed, and the solution was cooled to 24.0 °C with a cooling rate of 0.25 °C/min. Once the set point temperature was reached, the solution was maintained at that temperature undisturbed for 1.5 h. A stainless steel rod (5/32” diameter, 6.0” in length) was then used to contact the SAM at a force of 0.44 ± 0.08 N with a similar setup as described in a previous study.23 After the contact, the rod was withdrawn. The Petri dish was resealed and left undisturbed for another 2 h to allow any nuclei that had potentially formed to grow into crystals of visible sizes. The polymorph of the crystals on SAM, if any were formed after 2 h, was analyzed with a Kaiser Raman microscope equipped with a 785 nm exciting laser using a 600 grooves/mm grating and a 20× microscope objective. This objective gives a long working distance of 21 mm and a spot size of ∼25 μm. The spectra were collected from 100 to 4000 cm−1. The SAM surface with crystals on it was placed under the objective. Manual focusing of the Raman spectroscope was used to locate the interface position within the crystalline sample. A Raman spectrum was obtained using an exposure time of 2 s with three accumulations for each visible crystal generated (typically 1−20 visible crystals were generated for each experiment). In addition, the preferred orientation of the crystals on the SAMs was characterized using X-ray diffraction (XRD, PANalytical X’Pert PRO). The crystal morphology was visualized using an optical microscope (Nikon). SAMs used for ROY crystallization experiments included 4MP, MHDA, and 4MBP. Unfunctionalized gold substrates were also used as control. 10−12 independent experiments were performed for unfunctionalized gold substrates and each type of SAMs. The number of repeats, although not enough for quantitative analysis of induction time because of the stochastic nature of nucleation, was large enough to show a qualitative trend, as was the goal for this study. Crystallization of INA in the Presence of SAM Templates. INA crystallization experiments were performed at the concentration of 69.5 mg/mL. To prepare INA solution, desired amounts of solids were completely dissolved 18.0 mL of ethanol after the solution was heated up to 60 °C. The solution was then filtered (0.2 μm pore size) and transferred into a prewarmed glass Petri dish in which a SAM or unfunctionalized gold substrate was already placed. The Petri dish was then sealed, and the solution was cooled to 20.0 °C with a cooling rate of 0.25 °C/min. Once the set point temperature was reached, the solution was maintained at that temperature undisturbed for 1.5 h. A stainless steel rod (1/16” diameter, 6.0” in length) was then used to contact the SAM at a force of 1.3 ± 0.2 N with the same setup as with ROY experiments described above. After the contact, the rod was withdrawn. The Petri dish was resealed and left undisturbed for another 2 h. The polymorph of every visible crystal formed on SAM was then analyzed with a Raman microscope and XRD as described in ROY crystallization. Same as for the ROY crystallization experiments, preferred orientation and crystal morphology were analyzed by XRD and optical microscopy, respectively. SAMs used for INA crystallization experiments included 4MP and MHDA. Unfunctionalized gold substrates were also used as a control. A total of 11−15 independent experiments were performed for unfunctionalized gold substrates and each type of SAMs. Control Experiments with No Contacts. To verify that crystallization in the ROY and INA experiments were indeed induced by contacts, control samples were prepared in an identical manner and were subjected to the exact same procedures as described above for each system, except there was no contact by the stainless steel rod. No visible crystals were formed in the ROY solution for 48 h, and no visible crystals were formed in the INA solution for 1 week.

impractical for industrial applications. We instead use contact force to induce nucleation on heterosurfaces. It greatly reduces induction time while still largely maintaining the target polymorph. This study demonstrated and rationalized different results obtained when exerting a contact force on SAMs with different functional groups in two systems. In the first system, 5-methyl2-[(2-nitrophenyl) amino]-3-thiophenecarbonitrile (commonly known as ROY), we studied how nucleation frequency varies with the change. In the second system, isonicotinamide (INA), in addition to nucleation frequency, we investigated how functional groups on SAMs can influence polymorphism. Our results provide new insights into the fundamental understandings of contact-induced heterogeneous nucleation and the mechanism of contact secondary nucleation.

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EXPERIMENTAL SECTION

Materials. ROY was a gift from Eli Lily & Company and was used without further purification. INA with a purity of ≥99% was obtained from Sigma-Aldrich. Solvents ethanol and toluene were used as received and were of ACS reagent grade both with a purity of ≥99.5%. 4-Mercaptopyridine (4MP), 16-mercaptohexadecanoic acid (MHDA), and 4-mercaptobiphenyl (4MBP) were purchased from Sigma-Aldrich. Gold-coated (100 nm thick coating of gold) glass substrates were purchased from Evaporated Metal Films Corporation, New York, and used as a SAM substrate. Monolayer Preparation and Characterization. SAM surfaces were prepared by immersing gold-coated glass substrates in 10 mM solutions of 4MP, MHDA, and 4MBP in ethanol for 18 h at room temperature, following the SAM preparation procedures described by Yang et al.6 After they were removed from solution, the substrates were rinsed with copious amounts of toluene and then carefully blowdried with ultrahigh-purity nitrogen. Functionalization of Gold Substrates Was Verified with Contact Angle and Infrared (IR) Measurements. Contact angles were determined by the half angle measuring method, using a model 200 contact angle goniometer by Ramé-Hart Instrument Co. (Succasunna, NJ). All contact angles reported were the averages of 10 readings made on at least three independently prepared SAMs. The IR spectra of the bulk thiols were obtained with IdentifyIR, an FT-IR spectrometer (Toronto, Ontario). Spectra were acquired at 4 cm−1 resolution averaging 128 interferograms. The IR spectra of SAMs were acquired by reflection at an angle of incidence of 55° from the normal with p-polarized light using a Thermo Fisher Continuum FTIR microscope attached to a Thermo Fisher FTIR6700. Spectra were acquired in attenuated total reflection mode at 4 cm−1 resolution averaging 128 interferograms for each sample. Atomic Force Microscopy (AFM) Imaging. The morphology and roughness of SAMs were analyzed using AFM imaging. The images were obtained in tapping mode using Veeco Metrology Nanoscope IV instrument. Depth and roughness were analyzed using Nanoscope software. The results show that all SAMs are smooth and that different SAMs have similar roughness and topography. This is because the roughness of the plates is determined by the gold underlayer and not affected by the single layer of molecules added to the surface. See Supporting Information for detailed images and roughness measurements. Crystallization of ROY in the Presence of SAM Templates. ROY crystallization experiments were performed at two concentration levels: 66 and 68 mg/mL. To prepare ROY solutions, desired amounts of ROY solids were completely dissolved 2.5 mL of toluene after the B



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Calculations. The initial molecular models of ROY, INA, 4MP, MHDA, and 4MBP were built in the Materials Studio software, and atom types were assigned using COMPASSII force field.30 The geometry of each molecule was optimized in gas phase in a vacuum using the Smart algorithm in Materials Studio. The Smart algorithm is a cascade of the steepest decent,31 ABNR and quasi-Newton methods.32 Next, using the optimized structures, the models of five molecular complexes were built, namely, ROY···4MP, ROY···MHDA, ROY···4MBP, INA···MHDA, and INA···4MP. In order to minimize bias introduced by the initial orientation of molecules, the molecules were systematically rotated with respect to each other. In the case where different initial orientation yielded different optimized structures, the structure with the minimum energy was accepted. Following the described optimizations, the obtained atom coordinates were used in gas-phase DFT calculations. The geometry of all individual molecules and complexes was optimized, and energy was calculated using M06/6-31+G(d) level of theory in GAUSSIAN 09 computer program.33 See Supporting Information for figures of optimized individual molecules. The association energy was calculated as the difference in energy of the optimized complexes and combined energy of the optimized individual molecules: ΔE = Ecmplx − (Emol + ESAM), where Ecmplx is energy of the optimized complexes, and Emol and ESAM are energies of the optimized individual solute molecule and SAM molecule. The crystal structures of INA were analyzed using Mercury software (Mercury CSD 3.6, last updated July first, 2015).34 The Refcodes EHOWIH02 and EHOWIH01 were used to analyze the structure of INA Form I and Form II, respectively.35

mL, no nucleation was observed for 10 independent experiments performed on unfunctionalized gold substrates, suggesting the supersaturation level was low enough that the disturbance from contacts could not cause nucleation. However, identical procedures performed on SAMs at the same concentration of solution resulted in nonzero nucleation frequency, and in the case of MHDA and 4MBP, the nucleation frequency was significantly higher than that of unfunctionalized gold substrate control. The possibility that the thiol molecules had already induced heterogeneous nucleation prior to contact was ruled out by the control experiment that showed no crystals were formed for at least 2 days without contact. Therefore, it can be inferred that SAMs facilitate the organization of prenucleation clusters to be more favorable for nucleation than in the absence of SAMs. Prenucleation clusters organized by SAMs undergo an “accelerated” nucleation process due to contact forces. In other words, the organization of prenucleation clusters by SAMs lowers nucleation energy barrier significantly enough that nucleation induced by contact, which would otherwise not occur at certain conditions without the organization by SAMS, does take place. Figure 1 also shows nucleation frequency under the same conditions varies depending on the functional groups on SAM. In the case of the ROY system, MHDA and 4MBP are more effective at organizing the solute molecules into conditions more favorable for nucleation than 4MP. The variation in observed nucleation frequencies can be explained by differences in the energetics of ROY interacting with different SAMs. The SAM that interacts the strongest with ROY molecules should be the most effective at stabilizing prenucleation clusters and locally increasing ROY concentration and thus promoting nucleation. Essentially, enhanced nucleation frequency observed experimentally is a macroscopic manifestation of strong interactions between solute molecules and SAM. To rationalize the observed trend, we assumed that the most important ROYSAM interaction can be captured by modeling only the interactions of the molecular part of SAMs, namely, 4MP, MDHA, and 4MBP, with ROY molecules. See Figure 2. Thus, we computed the association energies for all three complexes, ROY···4MP, ROY···MDHA, and ROY···4MBP. The results, summarized in Table 2, show that the calculated association

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RESULTS AND DISCUSSIONS Nucleation Frequency: Crystallization of ROY in the Presence of SAM Templates. The frequency at which ROY crystals were observed at the end of each experiment for each type of SAMs was calculated for both supersaturation levels and summarized in Figure 1. At the lower concentration of 66 mg/

Table 2. Summary of Energetics of ROY interacting with different SAMs

Figure 1. Nucleation frequency of contact-induced nucleation of ROY on each type of SAM and unfunctionalized gold substrate (control) at two supersaturation levels.

complex

ΔE (kcal/mol) (SMART)

ΔE (kcal/mol) (DFT)

ROY···4MP ROY···MDHA ROY···4MBP

−9.32 −11.79 −13.33

−9.97 −9.88 −14.90

energies follow the same trend as experimentally determined nucleation frequency. The interaction of ROY···4MBP is ∼4 kcal/mol stronger than ROY···4MP, which corresponds to the

Figure 2. Optimized structures of the molecular complexes (a) ROY···4MP, (b) ROY···MDHA, and (c) ROY···4MBP. Blue dashed lines represent hydrogen bonds. See Supporting Information for a discussion on modeling the geometry of the complexes. C



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A previous study22 has shown that carboxylic acid typically promotes formation of chains of INA in ethanol because the carboxylic acid group favors association with the amide tail of INA. Although MHDA has a carboxylic group, the same study shows that it does not promote the chain arrangement sufficiently to overcome the dominance of dimers, and therefore Form II crystals are typically obtained in cooling crystallization on MHDA SAMs. Similar results were observed in this study of contact-induced nucleation as shown in Figure 3b, where 55% of experiments with MHDA as SAMs resulted in Form II upon contact. Interestingly, 9% of the experiments gave a mixture of Form I and II crystals, which echoes the theory that the carboxylic acid group does favor chain formation, and MHDA, with a carboxylic acid on a long alkane backbone, simply does not promote enough of those INA chain formations such that only a small fraction of experiments generated Form I mixed with Form II crystals. The SAMs of 4MP generated even more interesting polymorph outcomes. The previous study22 has suggested the pyridine group of 4MP favors interactions with the amide group of INA, and therefore the chain formation, which resulted in mostly Form I crystals in cooling crystallization on 4MP SAMs. In this study of contact-induced nucleation, Form I crystals were indeed observed in a total of 53% of experiments, as shown by the exploded wedges in Figure 3c, a much larger proportion than that observed in MHDA (9%) or unfunctionalized gold substrates (0%). However, among the experiments where Form I crystals were observed on 4MP SAMs, some were a mixture of Form I and II, as indicated by the dark gray wedge in Figure 3c. This result shows that 4MP is not always effective at organizing prenucleation clusters into chain formations. Indeed, 20% of the repeats generated pure Form II, as indicated by the black wedge. As in the case of ROY, we modeled the interactions of INA with SAMs by optimizing the molecular complexes presumably formed on the surface of the SAMs between the solute INA and the molecular part of SAMs, namely, 4MP or MDHA. See Figure 4. The molecular complex INA···MDHA is held together by a heterodimer based on hydrogen bonds formed between carboxylic −COOH group of MDHA and amide −CONH2 tail of INA. This formation resembles Form II of INA, which is consistent with the observation that the majority of crystallization on MDHA SAMs yielded pure Form II. On the other hand, the molecular complex INA···4MP is based on hydrogen bond between amino −NH2 group of INA and pyridine ring of 4MP, resembling Form I of INA. The fact that the polymorph outcomes of contact-induced nucleation in this study are largely similar to those of cooling heterogeneous nucleation study on SAMs indicates that SAMs serve as molecular templates in both cases that determine the organization of prenucleation clusters which eventually leads to the formation of crystals of a certain polymorph. A contact force imparts energy, increases mixing in the system, and accelerates the process of nucleation. However, contact-induced heterogeneous nucleation is also fundamentally different from undisturbed heterogeneous nucleation. The mechanism of undisturbed heterogeneous nucleation in organic small molecules system was studied in detail by Harano et al.13 using the single-molecule real-time transmission microscopy: a reactive surface or a functional group on a surface interacts with, or in their case chemically traps, a solute molecule referred to as “molecule zero”. The molecule zero then acts as a template and recruits other molecules to form a disordered

observation that nucleation frequency on 4MBP is higher than that on other SAMs or on unfunctionalized gold substrates. A similar nucleation frequency pattern was observed when the concentration of solution was increased to 68 mg/mL. At this concentration, supersaturation was high enough that the system sometimes nucleated even without the additional organization of solute molecules by SAM, although the nucleation frequency was still significantly higher in the presence of SAMs. The XRD and Raman measurements revealed that at both concentration levels, polymorphs Y and R (monoclinic refcode: QAXMEX0136 and triclinic QAXMEH0236) were obtained, but we did not observe any particular correlation between polymorphic outcome and types of SAMs. Polymorphism: Crystallization of INA in the Presence of SAM Templates. In the INA crystallization experiments, not only did nucleation frequency vary depending on the type of SAMs, but the polymorph of crystals obtained did as well. The results are summarized in Figure 3. Similar to results in the

Figure 3. Polymorph outcomes of INA crystallization induced by contact on (a) unfunctionalized gold substrate, (b) MHDA, and (c) 4MP.

ROY experiments, the INA solution with unfunctionalized gold substrates had the lowest nucleation rateonly 1 in 13 repeats nucleated upon contact, as shown by the colored wedge in Figure 3a. On the other hand, 64% and 73% of solutions with MHDA and 4MP nucleated upon contact, respectively. This result once again confirms that some SAMs are capable of organizing prenucleation clusters in such a way that it lowers nucleation activation energy. INA has five known polymorphs, among which Form II is the most stable at room temperature.35,37 According to the literature, in Form II crystals, the amide group of one molecule forms a dimer with that of a second molecule, while in other polymorphs, head-to-tail chains are connected through the amide and the pyridine group.22 In many solvents, INA selfassociates into both dimers and chains, and the competing process of cluster formation of the different associates dictate the polymorphic outcome. In ethanol in particular, dimers usually outcompete chains and Form II is favored.38 This explains why Form II crystals were observed in the 1 case out of 13 unfunctionalized gold substrate experiments that did crystallize, as shown in Figure 3(a). D



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Figure 4. Optimized structures of the molecular complexes of INA compared to the crystal structures of different INA polymorphs: (a) INA···4MP molecular complex, (b) chain-like Form I of INA, (c) INA···MDHA molecular complex, and (d) dimer in Form II of INA.

precursor cluster, or a dense liquid clusters as some would describe it.16 The cluster proceeds to become a crystal nucleus, and finally a crystal. The interaction between solute molecules and surfaces remains throughout process and can be so strong that it has been reported that gold plating was ripped off the glass substrates when crystals attached to SAMs were being removed.29 In contact-induced nucleation, on the other hand, crystals were not chemically attached to the SAM surface. Indeed, they do not seem to have any detectable chemical interactions with the SAM surface. Not only could crystals generated by contact-induced nucleation be easily removed from the SAM surface without resistance by a tweezer, Raman spectra also could not detect any interactions between crystals and the SAM functional groups (Figure 5). In collecting Raman spectra, the same procedure was followed as in the study of undisturbed heterogeneous nucleation which clearly showed signals associated with SAMs−INA intermolecular interactions (Figure 5(1)). Spectrum (1) in Figure 5 shows that when Form I INA interacts with the 4MP surface there is an additional peak in the -NH2 stretching vibrations region. However, spectrum (3) of Form I INA generated by contact-induced nucleation on 4MP is the same as that of pure Form I INA and lacks the additional peak indicating interaction with the 4MP surface. In other words, crystals generated by contact-induced heterogeneous nucleation are not chemically bound to SAM surfaces. It is possible that the first solute molecule attracted the SAM surface, or “molecule-zero”, has recruited some other solute molecules, but the new “recruits” have not had enough time to also develop chemical interactions with SAM. Therefore, when the contact force is exerted, the prenucleation cluster either breaks the interaction with molecule-zero, or molecule-zero breaks its interaction with SAM, and then the prenucleation cluster nucleates. It follows that the nucleus forms in solution and eventually settles back onto the heterosurface due to gravity and grows into a crystal. As a result, the preferred orientation of the samples should not be strongly influenced by SAMs. Indeed, the XRD powder patterns (Figure 6) show that the preferred orientation of crystals generated by contact-

Figure 5. Raman spectra of INA crystals showing the -NH2 stretching vibrations (3000−3125 cm−1) and pyridine ring breathing mode (975−1100 cm−1) vibrations: (1) interface region of Form I INA on the 4MP surface generated by undisturbed heterogeneous nucleation, (2) pure Form I of INA, (3) Form I INA on the 4MP surface induced by contact. Data of (1) and (2) were obtained from Kulkarni et al.22 Note that compared to (1), (3) does not have the additional peak positioned at higher wavenumbers, indicating a lack of interaction between the pyridine of the 4MP SAM and the amide group of INA induced by contact force.

induced heterogeneous nucleation varies from sample to sample. In addition, microscope imagining reveals that crystal morphologies are consistent with those expected from growth in solution and exhibit variations from crystal to crystal (see Supporting Information). The observation that crystals could be removed from SAMs easily, combined with results from Raman, XRD, and microscope imaging analyses, indicates that crystals obtained from contact-induced heterogeneous nucleation are simply resting on the surface of SAMs with random E



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Figure 6. XRD of (a) ROY crystal planes in contact 4MP in three repeat experiments, and (b) INA crystal planes in contact with 4MBP in two repeat experiments. Different samples are indicated with different colors.

upon the surface due to gravity. They do not form strong interactions with the surface, as indicated by random preferred orientation of the crystals. The presented study of contact-induced heterogeneous nucleation lends new insights into the mechanism of contact secondary nucleation. We replaced parent crystals with SAMs as template for nucleation. In essence, SAMs can be seen as parent crystals without a crystal lattice and concentration gradient in the boundary layer. Contact-induced nucleation on SAMs thus offers a unique opportunity to isolate the effect of functional groups during contact secondary nucleation. In the past few decades, contact secondary nucleation has been characterized as a microattrition process,39−45 a nucleation event taking place at the boundary layer of the parent crystal,46−48 or both.23,49 The results of this study showed that microattrition is not the only mechanism contributing to contact secondary nucleation since there was no parent crystal for microattrition to take place in this study, and yet nuclei were still generated. Functional groups alone are capable of attracting, stabilizing, and arranging solute molecules, which could result in nucleation upon contact.

preferred orientation, unattached to SAMs. These results suggest that contact-induced heterogeneous nucleation most likely takes place in solution, and nuclei subsequently fall onto the surface of SAMs due to gravity. The proposed mechanism for contact-induced heterogeneous nucleation is summarized and illustrated in Figure 7. As

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CONCLUSIONS In this study, by combining crystallization experiments, XRD and Raman analyses, and computational models, we proposed a likely mechanism of contact-induced heterogeneous nucleation on SAMs as hetero surfaces. We found that it is possible to induce nucleation at conditions where nucleation cannot be induced without the presence of the templates. Nucleation frequency is enhanced when there are strong interactions between the solute molecules and the templates. The templates are also able to organize molecules into structures most favorable for solute−template interactions, which could lead to nucleation of different polymorphs. These results show that contact-induced heterogeneous nucleation shares similarities with undisturbed heterogeneous nucleation in terms of attracting and stabilizing prenucleation clusters, but they are also fundamentally different in that crystals generated by the former are not chemically interacting with the templates. The results also show microattrition is not the only mechanism for contact secondary nucleation, considering that in our experiment there were no parent crystals so microattrition was not possible. Instead, the contact force can induce nucleation even if only appropriate functional groups are present. In terms of

Figure 7. Schematic of the mechanism of nucleation and crystal growth induced by contact force: (a) heterosurface submerged in solution, (b) “molecule zero” attaches to a nucleation site (red dot) of the surface, (c) formation of the disordered prenucleation cluster surrounding the “molecule zero” (inset: if no force is applied, solute molecules form more interactions with the surface, and undisturbed heterogeneous nucleation proceeds), (d) contact force disrupts clusters and induces nucleation, (e) formation of nuclei in solution, (f) crystals fall upon the surface due gravity but do not form strong interactions.

in undisturbed heterogeneous nucleation, the first step is attachment of “molecule zero” to a nucleation site (red dot) of the surface followed by formation of the prenucleation cluster surrounding the “molecule zero”. In the next step, the mechanisms bifurcate. If no force is applied, solute molecules form even more interactions with the surface, and nuclei form and stay attached to the surface (inset in Figure 7c) resulting in the crystals strongly bound to the surface (inset in Figure 7c). However, the introduction of contact force disrupts clusters and detaches them from the surface. Detached clusters form nuclei in solution that grow into crystals that eventually fall F



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technology applications, our method significantly shortens the induction time of templated heterogeneous nucleation, from days to hours, and controls the polymorphic outcome of crystallization.

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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.6b01284. AFM images and roughness analyses of SAMs, images of optimized structures of individual solute and SAM molecules, a discussion on modeling the geometry of solute−SAM molecular complexes, and microscope images of ROY and INA crystals (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

Financial support from DARPA through Grant No. N6600111-C-4147 is gratefully acknowledged. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Andong Liu at the MIT Gleason group for assistance with contact angle measurements, and Timothy McClure at the MIT Center for Materials Science and Engineering for assistance with IR measurements of SAMs.

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REFERENCES

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Mechanism of Contact-Induced Heterogeneous Nucleation - Crystal

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