Synthesis of Julolidines via Microwave Heating Tecia Grier, Shanina Sanders, PhD

Department of Chemistry, Spelman College, Atlanta, GA 30314

The synthesis of julolidine was attempted using the Discover LabMate Microwave for heating. Optimizations included the amount of starting material, the temperature of the solution, the power of the microwave, and the reaction time to determine the best route to improve the synthesis of julolidines and its derivatives. The main focus is to reduce the reaction time and produce better yields of the solution.

1. Abd El-Aal, H.; Khalaf, A.; El-Khawaga, A., J. Heterocyclic Chem. 2014, 51, 262 2. CEM Coporation . CEM Tomorrow's Science Today. 2010 . 11 09 2014 <http://cem.com/discover-sp.html>. 3. Gavvala, K.; Sasikala, W.; Segupta, A.; Dalvi, S.; Mukherjee, A.; Hazra P., Phys. Chem. Chem. Phy. 2013, 15, 330-340. 4. Goh, W.; Lee, M.; Joseph, T.; Quah, S.; Brown, C.; Verma, C., J. Am. Chem. Soc. 2014, 136, 6159-6162.

INTRODUCTION DISCUSSION

The reactions for the synthesis of julolidines were optimized using the control panel on the Microwave Synthesizer shown in Figure 1. The control panel allows methods to be formulated with different reaction times, temperature, power, and cooling time. Based on the results for previous trials, the determination for the methods for the next trials was made. Table 1 shows the trials performed for the synthesis of julolidines. Equation 1 shows the steps used to complete the synthesis involving a mixture of aniline, 1-bromo-3-chloropropane, and DMF shown in Figure 2. Figure 3 is the crude product from this reaction which is a result of a lower reaction time with a high power and temperature. Figure 4 shows the product once the workup was done. Results shown in Table 1 were compared to the standard julolidine 1H-NMR spectrum in Figure 6. It shows that the synthesis produces more product at a temperature of 200 ˚C and a power of 300 Watts. As you can see the product for Trial 10 has very similar peaks to the 1H-NMR spectrum in julolidine. The spectrum has the same number of signals with the integration and chemical shift. The 1H-NMR spectrum for Trial 9 indicates that a by-product or intermediate is the major product. It only has trace amounts of the final product. This trial was conducted at a low reaction time and temperature thus supporting the results from Figure 7 where a higher temperature and power are used.

METHODS/ RESULTS

Thanks to the Department of Chemistry and Biochemistry Research Initiation Award and Corning for the support of this project .

ACKNOWLEDGEMENTS

REFERENCES

ABSTRACTJulolidines are heterocyclic aromatic compounds with one ring junction nitrogen atom, classified as molecular rotors. molecular rotors have been used as sensors, with the capability of measuring the viscosity in cell membranes to detect diseases such as Parkinson’s and Alzheimer’s. The possibility of julolidine and its derivatives being used for photoconductivity, as anesthetics, dyes, as potential antidepressants and tranquilizers, and used to refine the color strength in photography has induced an interest to research the substance and its properties. The development of valuable and efficient tactics for the structure of these ring systems remains a significant task. Few synthesis methods for the synthesis of julolidine and its derivatives have been reported. One method of conducting the reaction that has not been reported in the literature is using a microwave synthesizer. The microwave synthesizer is known to reduce reaction times, about 10-1000 times faster and produce better yields than conventional heating. This device provides monitoring and control of temperature, pressure, and stirring to ensure maximum safety and reproducibility in the lab. The microwave synthesizer could make the reaction more energy and time efficient, produce better yields, reduce the amount of hazardous solvents, and enhance safety. Using the microwave synthesizer, optimizations for the trials will include the amount of starting material, the temperature of the solution, the power of the microwave, and the reaction time to determine the best route to improve the synthesis of julolidines and its derivatives. The microwave will allow more ability to control the experiment by introducing new variables into the experiment to produce better results.

Julolidines consist of electron donating and electron withdrawing units, which are conjugated in the planar ground state. When light hits the compound it becomes excited and takes on a twisted structure, which disrupts the conjugation. It then relaxes through fluorescence emission or a non-fluorescent relaxation pathway.4 These molecular rotors can be highly sensitive to the environment. The compound will undergo fluorescence in a viscous environment; the non-fluorescent relaxation pathway is prevented. This allows compounds in the molecular rotor family to be used as fluorescent dyes and sensors in biological systems. Further analysis of this family of compounds is needed to analyze their potential as sensors in applications relevant to biological and energy fields. However, in order to study these compounds an efficient synthesis strategy is needed to produce a variety of substituted julolidines. Varying substituents can be on the piperidines ring, aromatic ring, and the vinyl carbon.3 The aim of this project is to provide more efficient synthesis routes to form a variety of julolidines. The current synthesis for julolidines is limited by the harsh reaction conditions. The least expensive method of making these compounds is from aniline derivatives. The general procedure involves refluxing the reactions in dimethylformamide for 14 hours. The average yield reported is about 50 percent. Another route involves alkylation of a 1,2,3,4-tetrahydroquiline with 3-chloro-1-bromopropane.1 However, tetrahydroquinolines are very expensive and not practical starting materials. Instead of tetrahydroquinoline, aniline will be used to produce the julolidine derivatives reducing the preparation cost. Various reaction conditions will be tested to synthesize the juloliodines using the microwave to improve the results. The microwave will allow more ability to control the experiment by introducing new variables, such as the temperature of the mixture, the power of the microwave, the cooling time, the pressure applied, and the reaction time. The microwave synthesizer is known to reduce reaction times, about 10-1000 times faster than current methods.2 Instead of waiting 12 hours for the reaction to completely reflux, the microwave synthesizer may allow shorter heating periods or a combination of heating and cooling periods.

Equation 1: Current Synthesis of Julolidine from Aniline

Figure 1: Microwave Control Panel Figure 2: Starting Material

RESULTS

Table 1: Trials for Julolidine Synthesis

Trials Time (mins)

Temperature (°C)

Power (Watts)

Increments

NMR Results -major peaks

1 60 200 150 1 Product

2 30 150 300 1 Product3 20 200 150 1 Product4 60 200 300 3 Product5 60 150 150 3 Intermediate6 60 150 300 3 Intermediate7 30 150 300 1 Intermediate8 20 150 300 1 Intermediate9 60 150 300 1 Intermediate

10 60 200 300 1 Product

FUTURE PLANS The next steps include checking the yields of the product from the best trials. Once the reaction is optimized other aniline derivatives, shown in Figure 5, can be screened in the reaction to test the scope.

Figure 3: Crude Product

Figure 4: Product

Figure 6: Julolidine 1H-NMR Spectrum

Figure 7: Julolidine 1H-NMR Spectrum of Trials

Trial 10: 60 minutes, 200 °C, 300 W (Crude Product)

Trial 10: 60 minutes, 200 °C, 300 W (Clean Product)

Trial 8: 20 minutes, 150 °C, 300 W (Crude Product)

Figure 5: Selected Aniline Derivatives for Julolidine Synthesis