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Use of Programmed Damped Temperature Cycles for Deracemization of a Racemic Suspension of a Conglomerate Forming System Kittisak Suwannasang, Adrian Evan Flood, Celine Rougeot, and Gérard Coquerel Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00028 • Publication Date (Web): 20 Mar 2017 Downloaded from http://pubs.acs.org on March 23, 2017

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Organic Process Research & Development

Use of Programmed Damped Temperature Cycles for Deracemization of a Racemic Suspension of a Conglomerate Forming System Kittisak Suwannasang1,2, Adrian E. Flood*,1, Celine Rougeot3, Gerard Coquerel3 [1] Department of Chemical and Biomolecular Engineering, School of Energy Science and Engineering, Vidyasirimedhi Institute of Science and Technology, Rayong 21210, Thailand. [2] School of Chemical Engineering, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand. [3] Normandie Université, Crystal Genesis Unit, SMS, EA 3233, Université de Rouen, F-76821 Mont-Saint-Aignan Cedex, France. Email : [email protected] KEYWORDS: Deracemization, Chiral resolution, Damped temperature cycles, Conglomerate forming system. ABSTRACT: The current research has developed a potential route towards process optimization for deracemization of a racemizable conglomerate forming system. The use of damped temperature cycles – where the magnitude of the temperature cycles is reduced as the enantiomeric excess (e.e.) in the solid phase increases – is a promising methodology for optimizing the temperature cycle induced deracemization process. This process requires significantly less time and energy to reach an enantiopure state compared with the use of constant amplitude temperature cycles. There was evidence of some crystal breakage occurring in the system, however the limited amount of breakage did not produce any change in the enantiomeric excess in the solid phase in the absence of temperature cycles in the system. Hence, the primary mechanism in this process is neither Viedma ripening nor Ostwald ripening. SEM micrographs of the crystals taken during the series of temperature cycles show that the amplification of the e.e. in the solid phase is caused by dissolution and growth phenomena induced by the temperature cycles. The promotion of the larger or faster growing crystals at the expense of the smaller or slower growing crystals during the cycles and entrainment from a mother liquor having e.e.= 0 are both responsible for this deracemization.

INTRODUCTION

An enantiopure phase can be obtained from a racemic mixture via several techniques (e.g. chiral chromatography, biocatalytic processes, and crystallization among others). In 2005, Viedma first achieved a complete symmetry breaking of an initially racemic suspension of sodium chlorate by continuous grinding– a process now known as Viedma ripening.1 A short time later the groups of Vlieg and Blackmond successfully adapted the method for deracemizing of an intrinsically chiral compound via a combination of abrasive grinding and racemization in solution.2,3 This process has been rapidly extended to other organic chiral compounds.4-11 There has been several attempts to explain the mechanism behind attrition-enhanced deracemization.12-30 There is a fairly general consensus on the role of capture of clusters of the ‘good’ chirality docked on the surface of crystals. Other processes to achieve homochirality in the solid phase have also been proposed, and fluctuations in temperature or energy is critical in most of these processes.31-37 The use of ultrasound for deracemization38 and several other methods to reach a pure enantiomorph have also been demonstrated.39-42 Recently, an interesting process that combines grinding and temperature fluctuations has been proposed.43 One of the simplest method to access a pure crystalline enantiomer from a racemic suspension of a chiral organic conglomerate-forming compound was recently proposed by our group.31 The method involves temperature cycling of a suspension of the conglomerate forming compound with fast racemization occurring in the liquid phase.

Repeated changes of temperature induce partial dissolution of crystals in the suspension during the heating periods and a recrystallization of the remaining crystals during the cooling periods, and this results in a single enantiomorph product after a number of temperature cycles. While both the current process and Viedma ripening appear to rely on some form of crystal growth and dissolution process, Viedma ripening appears to occur mainly due to the attrition and breakage caused by strong collisions between crystals and beads while the current process relies on changes in temperature to achieve the dissolution and growth. The growth and dissolution cycles caused by temperature changes are the main mechanisms occurring in systems where the crystals in the suspension move through alternate supersaturated and undersaturated situations (in time or in space). Deracemization by temperature cycles is important in an industrial perspective, but is also important from a theoretical perspective because it highlights a key mechanism occurring in the deracemization process, dissolution and recrystallization phenomena. A modified method to optimize the temperature cycle induced deracemization process is proposed in this article. In our previous work, the maximum and minimum temperatures of the temperature cycles were maintained at constant values throughout the entire period of the experiment even though the e.e. of the suspension was increasing over time.31 This strategy seems to be suboptimal in terms of operating time because it is not necessary to destroy more of the preferred crystals than the remaining crystals of the counter enantiomer once the symmetry of the crystalline

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phase has been broken and the evolution of e.e. is accelerating. Hence, a new method has been investigated here, making use of the autocatalytic nature of the deracemization process to enable the use of smaller and faster cycles once the initial symmetry breaking has occurred.

Figure 1. (a) Chemical Structure of Cl-TAK. (b) Chemical Structure of Me-TAK. The original study of deracemization by temperature cycling was carried out using 1-(4-chlorophenyl)-4,4dimethyl-2-(1H-1,2,4-triazol-1-yl)pentan-3-one (ClTAK), Fig. 1a. This was used as a model compound because it is rapidly racemized in the presence of a base and is a stable conglomerate compound.44 To extend the temperature ripening technique to deracemization of other racemizable conglomerate compounds, 4,4dimethyl-1-(p-toluyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3one (Me-TAK), Fig. 1b, was chosen to be a model material for this study. In our previous study, the experimental results of temperature cycle induced-deracemization show a sigmoidal behavior in the evolution of e.e. The e.e. slowly increases at the beginning of the process, then rapidly evolves after reaching a breakthrough point, ca. 5% e.e., and then slowly approaches the pure enantiomorph after reaching ca. 90% e.e. The rate of change of the e.e. during thermal cycling can be modified by adjusting the magnitude and periodicity of the temperature cycles as the e.e. increases. In the current study the temperature program (TP) was set to have large changes for the initial cycles to initiate the symmetry breaking in the crystalline phase; then the TP was adjusted to have smaller temperature variations in later cycles – thus reducing the time required for a cycle – when the e.e. was high enough that the autocatalytic effect was substantial. The modification of the TP proposed in this study is an effective route to optimize the process of temperature cycle induced-deracemization by reducing the time required and energy consumption, and obtaining homochiral crystals from a racemic suspension via a simple process operation.

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Starting Crystal Prepared by Solvent Evaporation (RM1). Me-TAK was totally dissolved in a methanol/water mixture (80/20 %wt) in the presence of NaOH (8 g per kg of solvent) as a racemizing agent. The solution was evaporated at 50°C under a vacuum of 270 mbar. Solids were washed with a sufficient amount of water to remove the rest of the sodium hydroxide. MeTAK is essentially insoluble in water, so this washing did not dissolve a significant amount of the Me-TAK. The solids were then dried in an oven at 40°C. The preparation of this starting material is similar to the preparation of the starting material used in the Cl-TAK experiments. 31 Starting Crystals Prepared by Fast Cooling (RM2). 1.8 g of Me-TAK collected from RM1 was totally dissolved in 25 g of methanol/water mixture (65/35 %wt) in the presence of NaOH as a racemizing agent (0.2 g, i.e., 8 g per kg of solvent) at 35°C. The solutions were then filtered using 0.2 micrometer pore size filters and added into a 50 mL round-bottomed thermostatted flask at 35°C. The undersaturated solution was stirred by an oval magnetic bar operated at 500 rpm for 10 min to ensure that no nuclei remained in the system. Then the solution was cooled rapidly down to 20°C using a cooling rate of 1 °C/min. Deracemization Experiments. 1.8 g of Me-TAK, 25 g of methanol/water mixture (65/35 %wt), and 0.2 g of NaOH were chosen as a standard solution for the MeTAK experiments. One cycle in a loop of TPs consisted of four steps (Fig. 2a); holding at 20°C for 5 min, heating up to the upper temperature with a heating rate 2°C/min, holding at the upper temperature for 5 min, and then cooling down to 20°C with cooling rate 10°C/ 45 min. TP1 and TP2 use steady temperature cycles throughout the experiments (no damping pattern). The distinction between TP1 and TP2 is the maximum temperature in a cycle; TP1 has a maximum temperature of 25°C, while TP2 has a maximum temperature of 30°C (Fig. 2a). TP3 is a system of damped temperature cycles, having large swings for the initial cycles, followed by smaller temperature variations in later cycles as depicted in Fig. 2b.

EXPERIMENTAL SECTION

Materials. Racemic 4,4-dimethyl-1-(p-toluyl)-2-(1H1,2,4-triazol-1-yl)pentan-3-one (Me-TAK) was synthesized according to an efficient four-step method described elsewhere.45 Distilled water was used for deracemization experiments. HPLC-grade n-heptane and ethanol, and reagent-grade methanol were purchased from Fisher Scientific.


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B5

(a) 100 B4

80

% e.e.

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60 B3

40 20

B2 B0

0 0

A0

B1

10

A2

A1

20

A3

30

40

A4

50

A5

60

70

Time (h)

Figure 2. (a) Schematic representation of cycles in the temperature programs of TP2. TP1 is a similar set of cycles, however with a maximum temperature of 25°C. (b) Temperature cycles in the program TP3. In this TP there is a decrease in the upper temperature of the cycles as time (and e.e.) increases.

RESULTS AND DISCUSSION

Based on previous work it is expected that the particle size distributions of the two enantiomers, small imbalances in the initial masses of the two enantiomorphs in the suspension,1 impurities,46 etc. may have a strong effect on the symmetry breaking of an essentially racemic mixture of two enantiomorphs. To prevent a bias in the results, the starting crystals of experiments I, II, III, and IV were produced in the same batch using the preparation method RM1 as described in the experimental section. In the first experiment (Exp. I), the effect of grinding was investigated. 1.8 g of Me-TAK obtained from RM1 was partially dissolved in 25 g of methanol and distilled water (65/35 %wt) mixture in the presence of 0.2 g NaOH as a racemizing agent at 20°C. The suspension was gently agitated using an oval magnetic stirrer bar operated at 500 rpm to produce a uniform suspension. No temperature program was applied to this mixture.

Figure 3. Effect of the temperature programs on the deracemization of Me-TAK. (a) Evolution of e.e. versus time, (b) Evolution of ln (e.e.) versus time, (c) Evolution of e.e. versus the number of heating-cooling cycles. ● Experiment I – constant temperature at 20°C, ○ experiment II - TP1 (no damping effect), ▼ experiment III - TP2 (no damping effect), ∆ experiment IV - TP3 (damping effect). The time required for TP3 is represented by the yellow box; the additional time required for TP2 is represented by the green box. Labels on Fig. 3(a) indicate similarly named SEM photos that were taken at that point in the experiment.



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The results of the constant temperature experiment (shown in Figure 3) demonstrate that there is no evolution of e.e. over a period of 70 hours in the absence of temperature cycles (the full duration of this experiment). Although using the magnetic stirrer reduces the crystal size (producing some breakage of the thin plate-like crystals) as can be seen in Fig. 4A, the e.e. does not significantly change from 0% e.e. as is shown in Fig. 3a. These results are similar to the experimental results in our previous article31 and also indicate that the temperature induced-deracemization does not occur through breakage and Ostwald ripening as was initially proposed for the process of Viedma ripening. Hence, Ostwald ripening and size-dependent solubility are not considered as primary mechanisms in deracemization due to temperature cycles. However, the grinding may act as a particle size control of the enantiomorphs in the system and might promote the dissolution/crystallization phenomena induced by TP. To prove the potential of TP on the deracemization of Me-TAK, Exp. II was carried out under the same operating condition as Exp. I, excepting that temperature cycles (TP1) were used throughout the experimental period. The results indicate that TP1 led to rapid symmetry breaking of the enantiomorphs, obtaining an enantiopure suspension in around 80 cycles or ca. 50 h (Fig. 3c). These results once more demonstrate the ability of temperature cycles to induce complete symmetry breaking in systems where a conglomerate forming system undergoes solution phase racemization. SEM micrographs of crystals during a constant temperature experiment (Exp I) and a temperature cycle experiment (Exp. IV) are shown in Fig. 4. Labels on the photos in Fig. 4 correspond to the labels indicated on the evolution of e.e. in Fig. 3a.

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Figure 4. SEM micrographs of samples from Exp. I and Exp. IV. A) Annealing under stirring without temperature cycles. Labels A0-A5 correspond to the arrows indicated on Fig. 3a (● Exp. I). B) Temperature inducedderacemization with damped cycles. Labels B0-B5 correspond to the arrows indicated on Fig. 3a (∆ Exp. IV). The white scale bars on A0 and B0 are equivalent to 100 µm, with all micrographs having the same magnification. The exchange of matter between the liquid and solid phase is an important driver of deracemization and this exchange can be promoted through changes in temperature. Temperature programs were used on the system to increase the variation of temperature and thus to enhance the amount of mass exchange between the solution phase and the crystal phase. The crystals obtained from the temperature cycling system have larger sizes, smoother surfaces, and more clearly visible edges than the crystals obtained from the constant temperature system, as shown in Fig. 4B. This shows the effect of the dissolution and growth cycles is more significant than the small abrasion effect occurring in this system. It was shown in the study of Cl-TAK31 that the evolution of e.e. was accelerated when a higher percentage of the mass of remaining crystal was dissolved by the temperature programs. TP2, which has a larger temperature swing, was thus applied throughout the entire period of experiment III. The amount of crystal in the initial suspension and the operating conditions of experiment II and III are the same except for the magnitude of the temperature swing and therefore the percentage of crystal dissolved during the heating period of a cycle. In Exp. II ca. 26% of the crystal in suspension was dissolved during the heating part of the cycle, and in Exp. III ca. 68% was dissolved. The results of these experiments are qualitatively similar to the experimental results for the deracemization of Cl-TAK. The time required to reach complete chiral suspension purity is shorter when the fraction of the suspension dissolved in the heating part of the cycle is high, as shown in Fig. 3a. However, the use of a TP with a constant temperature difference between the low and high temperature of the cycles, as used in the previous study, does not seem to be optimal operation. When the symmetry breaking has advanced significantly, so that the amount of one of the enantiomorphs is significantly larger than the amount of the other enantiomorph, the amount of crystal dissolved in a cycle can be reduced to prevent excessive dissolution of the major enantiomer, thus enhancing the deracemization rate. Indeed, having a larger number of crystals of the dominant enantiomer could enhance the effect of entrainment.31 Thus, TP3 was developed to accelerate the evolution of e.e. by reducing the time requirement of the cycles used after the initial symmetry breaking caused by the larger temperature cycles. TP3 consisted of temperature changes twice as great as that used with TP2 for the initial cycles, in order to initiate the symmetry breaking in the solid phase, and smaller changes (by reducing the high temperature in the cycle) after the initial symmetry breaking since the process has


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Organic Process Research & Development already reached the point where the auto-catalytic effect has become significant. At this point, smaller and shorter cycles (as shown in Fig. 2b) will be more efficient. It can be noted that while TP3 requires less time to reach an enantiopure solution, it uses approximately the same number of cycles. The major effect of the damping is to reduce the cycle time rather than decreasing the number of cycles required. However, the program TP3 is much more effective than TP2. The experiment using TP2 can achieve an enantiopure state within ca. 31 h, while the experiment using TP3 can achieve the same state within ca. 24 h. In both experiments 10 h is required to achieve take-off from the racemic mixture and it is fairer to compare the time required between the time of take-off and the complete deracemization; in Fig. 3a the time required for TP3 is represented by the yellow box (ca. 14 h), and the additional time required for TP2 is represented by the green box (ca. 7 h). Thus, the undamped temperature cycle requires about 50% longer time to deracemize the mixture compared to an unoptimized damped temperature cycle. This clearly demonstrates the significant advantage of the damping of the cycles, and suggests attempts to find an optimum damping profile will bring important benefits.

Figure 5. Effect of temperature cycles on deracemization of the compound initiated via nucleation by fast cooling (a) Evolution of e.e. versus time, (b) Evolution of ln (e.e.) versus time, (c) Evolution of e.e. versus the number of heating-cooling cycles. ● Experiment V – TP1 (no damping effect), ○ experiment VI – TP3 (damping effect). The next two experiments (Exp. V and Exp. VI) were performed using an initial suspension produced by the RM2 procedure. In this case the initial solution contained an equal amount of both enantiomers due to a swift racemization reaction. The solution was then cooled to 20°C as fast as possible (1°C/min) in order to generate nuclei for the initial crystals in the suspension. The two enantiomorphs in the initial suspension would be expected to have similar populations. Exp. V and Exp. VI were carried out with a damped temperature cycle pattern (as depicted in Fig. 2b), and a constant amplitude pattern (with the upper temperature of the cycles at 25°C) respectively. The results of these experiments are shown in Fig. 5. These two experiments show that the evolution of e.e. still tends to be an exponential increase to a final state. It could be noticed that the use of a damped TP improves the temperature induced-deracemization process since this temperature pattern can accelerate the evolution of e.e. in suspension effectively as shown in Fig. 5a. However, this effect may be exaggerated here; the first 12 h of the damped cycle experiment has a temperature difference of 10°C in the cycle, and there is an 8°C temperature difference for an addition 11.5 h. After this period the deracemization is almost complete. The constant amplitude cycle experiment uses a 5°C temperature difference, and hence may be expected to be slower during the initial period of the experiment in comparison to the damped cycle experiment. The final product depends on the starting raw material as shown in Table 1. Experiments were performed with two different starting crystal populations, produced using RM1 (evaporation of solvent), and RM2 (rapid cooling). The RM2 seeds were produced in the deracemization vessel at the beginning of each experiment (i.e. a new batch of initial suspension was created at the start of each experiment). This tends to create a different bias in the starting suspension for each new experiment, and



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therefore the direction of the deracemization will appear random. Two batches of crystals for the starting suspension were created using RM1; RM1-Batch 1 was used for 5 experiments and RM1-Batch 2 was used for two experiments.

racemic mixture of the two enantiomorphs to pure enantiomeric crystals may thus originate from the history of nucleation events of the two enantiomorphs.

The results show that a tiny amount of initial asymmetry controls the outcome, even at very small levels of asymmetry – note that the starting e.e. in the crystal phase for the experiments was measured as zero within the measurement uncertainty. In the case of experiments performed using a single batch of crystals produced by RM1 all experiments using the same batch resulted in the same enantiomorph as the product. In the case where different batches were used to produce the initial suspensions (RM2) then both outcomes occurred. The results also show that although the measured initial e.e. was zero, it does not guarantee that there is not a very small level of asymmetry in the crystalline phase. The very small asymmetry in the e.e. of the initial seeds (in terms of crystal size distribution and/or growth rate dispersion), which were produced by a rapid nucleation event, could be in terms of the sizes of the initial particles, the initial number of particles, or even in the growth rate distributions of the initial particles.

(A)Experiment V – TP1 (no damping effect)

Table 1. Enantiomer Obtained as the Final Product from the Temperature induced-Deracemization Experiments. The numbers represent the number of experiments producing this result. Final product analysis Starting material

Peak 1 of HPLC

Peak 2 of HPLC

Seed from RM1-Batch 1

0

5

Seed from RM1-Batch 2

2

0

Crystal population produced via RM2

2

4

One of our hypotheses is that the formation of the nuclei of the two enantiomers occurs at different times and/or different conditions, causing the later nucleating enantiomer to nucleate at a lower supersaturation.31 This stochastic process of nucleation results in a difference in the perfection of the crystalline structure between the two enantiomorphs, which leads to differences in crystal growth rate activities and/or a small imbalance in mass, in the initial numbers of the two enantiomorphs, or crystal size distributions of the two enantiomorphs. This memory effect indicates that the symmetry breaking of the crystals may originate from the nucleation events and history of growth.47,48 A difference in the crystal growth activities of the enantiomorphs may be considered as one of the possible sources of symmetry breaking toward a complete deracemization. The mechanism of temperature-induced deracemization starting from a

(B) Experiment VI – TP3 (damping effect)

Figure 6. SEM photos of samples taken during the experimental period of Exp. V and Exp. VI. A) Deracemization with constant temperature cycles. B) Temperature induced-deracemization with damped temperature cycles. Labels A0-A2 and labels B0-B5 correspond to arrows indicated on Fig. 5a for Exp. V and Exp. VI, respectively. The white scale bars on A0 and B0 are equivalent to 100 µm, with all micrographs having the same magnification. The SEM pictures of the samples of experiments Exp. V and Exp. VI show a larger size of the final product in comparison to their initial suspension as shown in Fig. 6. The crystal sizes of product from the damped temperature cycles system were slightly decreased, as seen in Fig. 6 (B5), due to having small temperature cycles at the final state of deracemization in the damped temperature cycle system. This increases the significance of the attrition effect compared to the effect of crystal growth towards the end of the experiment. The SEM pictures also indicate that the evolution of the deracemization of enantiomorphs is strongly dependent on the exchange of solute molecules between the solution phase and the solid phase, as we can see in the micrographs that the crystals have large size, good shape, and clear edges, indicative of a crystal growth driven process. Four further experiments were carried out using initial crystal populations produced using RM2 with the same operating conditions as Exp. V and Exp. VI. The results indicate that the outcome of each batch is random, as shown in Table 1. These results indicate that a random discrepancy in the nucleation event is likely to be responsible for the possibility of the temperature cycle induced deracemization.


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Organic Process Research & Development racemizing agent. The suspension was then filtered to separate the crystals from their mother liquor. The remaining sodium hydroxide on the crystals was washed off using a sufficient amount of water. Then the crystals were separated into two parts. The first part was used as the initial particles of Exp. VII. The initial solid phase for Exp. VIII was created from the second part of the preliminary preparation by totally dissolving the crystals in methanol without the racemization agent (NaOH). The solution was then placed under vacuum in order evaporate the solvent. The starting crystals of Exp. VII were thus smaller than the starting crystals of Exp. VIII as shown in Fig. 8.

(A)Experiment VII – Small crystals in the initial suspension.

(B) Experiment VIII – Large crystals in the initial suspension.

Figure 7. Effect of the initial size of seeds on deracemization. (a) Evolution of e.e. versus time, (b) Evolution of ln (e.e.) versus time, (c) Evolution of e.e. versus the number of heating-cooling cycles. ● Experiment VII – small seed size, ○ experiment VIIII – large seed size. Two experiments were conducted to investigate the effect of the crystal size of the initial suspension. The starting materials of both experiments were prepared in the same batch by anti-solvent addition; distilled water was added into the filtered unsaturated solution in the presence of a

Figure 8. SEM pictures of samples taken during the experimental period of Exp. VII and Exp. VIII. A) Small crystal size in the initial suspension. B) Large crystal size in the initial suspension. Labels A1-A6 and labels B1-B6 correspond to arrows indicated on Fig. 7a for Exp. VII and Exp. VIII, respectively. The white scale bars on A0 and B0 are equivalent to 100 µm, with all micrographs having the same magnification. The rate of deracemization differs according to the initial crystal size as shown in Fig. 7b. The results show a parallel trend of the curves of ln(e.e.) = f(t) for Exp.VII and Exp. VIII. This means that the evolution of e.e. is not disturbed by the size of the starting crystals. However, the time required to reach the complete deracemization for Exp.VIII is longer than for Exp.VII. This may be due



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to the unpredictable time of the breakthrough point of the deracemization, which is still an interesting point for investigation. The SEM photos of Exp.VIII show the effect of grinding is high at the initial part. This is due to the fact that breakage is size dependent – large crystals tend to break at much larger rates than fine ones.49 During the major part of the temperature cycling induced-deracemization, however, the effect of temperature cycles is much higher than the grinding as discussed above. The SEM pictures show that crystals remain at the certain size during the increase of the e.e. as shown in Fig.8.

CONCLUSIONS

Using a damping pattern in the temperature program is shown to result in an improved operation of the temperature induced-deracemization process, greatly reducing the operating time required for complete deracemization. The number of temperature cycles required is less than for undamped TPs, however, the major improvement seems to be that later cycles can be conducted more rapidly (due to the low temperature change required) allowing a larger number of cycles in a smaller period of time. This indicates that the dampedtemperature cycles should also reduce the energy consumption of the deracemization process. The amplification of the e.e. by temperature cycles is not induced by the grinding effect but rather by successive small entrainment effects at constant e.e. = 0 in the mother liquor. Nevertheless, this work also shows that small particles are also beneficial to a fast deracemization. ■ AUTHOR INFORMATION Corresponding Author *Phone : +66 (0) 33 01 4253. Fax : +66 (0) 33 01 4445. E-mail : [email protected]. Note The authors declare no competing financial interest.

ACKNOWLEDGMENTS

This work was financially supported by the Thailand Research Fund (TRF) in collaboration with Suranaree University of Technology (SUT) through the Royal Golden Jubilee Ph.D. Program (1.C.TS/51/B.1) and the University of Rouen. We also thank Vidyasirimedhi Institute of Science and Technology (VISTEC) for a Post-Doc fellowship. SUPPORTING INFORMATION Supporting information available includes experimental procedures for the analysis of e.e. using HPLC, solubility data for Me-TAK under the conditions used for the

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experiments, and a note on the definition of e.e. used in this study.

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TOC Graphic


Use of Programmed Damped Temperature Cycles ... - ACS Publications

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