The use of non-aqueous solubility to control reaction outcomes

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Evan Curtin from the Bradley Research Group at Drexel University presented a poster at the Research Day for the College of Arts and Sciences on April 5, 2011. The project involves the synthesis of aromatic imines and the measurement of their solubility to select an optimal solvent for their formation.

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The use of non-aqueous solubility to control reaction outcomes

  1. 1. The Use of Non-Aqueous Solubility to Control Reaction Outcomes<br />With knowledge of the solubility of the reactants and products, we can choose a solvent to optimize the reaction and isolate the product through simple filtration. Solubility data was determined via experimentation and was extrapolated along with a melting point to predict solubility in a variety of solvents at different temperatures. Specifically, this information will be used to optimize the Ugi reaction. Information pertaining to the Ugi reaction is obtained by investigation of imines, which are intermediates in the Ugi reaction. Imines can be synthesized by reactions of aldehydes and amines, reactants that can be easily obtained. <br />Abstract<br />Progress<br />Malaria <br />The Importance of Solubility<br />Obtaining Solubility Data<br />What Comes Next?<br />References<br />Advisor: Professor Jean-Claude Bradley<br />Evan Curtin <br />Creating a Saturated Solution <br /><ul><li>To be certain that a solution is saturated, the solute must completely dissolve first, then precipitate out
  2. 2. The supernatant will be saturated
  3. 3. Find a solvent in which the reactants are soluble and the products insoluble
  4. 4. Run the reaction
  5. 5. Simply filter to get a pure product
  6. 6. No further workup is needed, saves time</li></ul>Mix solute and solvent so that the solute doesn’t dissolve completely<br />Heat mixture until it equilibrates<br />Decant if necessary<br />Let cool to room temperature<br />If no precipitate forms, blow air onto solution to evaporate solvent<br />Decant off the supernatant, which will be saturated<br />Smaller sample size is quicker to equilibrate (done in 15 minutes)<br />ONSexp207: Solutions heated then cooled, 1,2,4 precipitated. Later used air to precipitate 3<br />(Ref: “Synthesis of compounds ranked 55-124 from library DEXP014-V2B”)<br />SAMS NMR Method for Determination of Solubility<br />(Ref: “Open Notebook Science Web Services.”, “Determination of solubility of sample 1A from UCExp262 in toluene, acetonitrile, THF, and chloroform.” )<br /><ul><li>So far, 2 imines have been successfully synthesized
  7. 7. Solubility of benzalaniline in ethanol was found to be 1.3M
  8. 8. Solubility of N-Vanillylidene aniline was found in ethanol, toluene and acetonitrile (0.07M, 0.04M, and 0.08M, respectively)</li></ul>Extrapolating RT Solubility and Melting Point<br /><ul><li>SAMS = Semi Automated Measurement of Solubility
  9. 9. Online web service created by Professor Bradley (Drexel, Philadelphia, Pennsylvania) and Professor Andrew Lang (Oral Roberts University, Tulsa, Oklahoma)
  10. 10. Uses a Googledocs spreadsheet, available to the public
  11. 11. Create a saturated solution of solute in a solvent
  12. 12. Obtain HNMR spectra of the saturated solution
  13. 13. Upload the spectra in JCAMP-dx format
  14. 14. Specify solute and solvent peaks, and the number of corresponding H’s
  15. 15. Enter density and molar mass for the solute and solvent (predicted densities from Chemspider.com are commonly used for solids)
  16. 16. Spreadsheet automatically calculates molarity
  17. 17. Life threatening disease caused by the parasite plasmodium falciparum
  18. 18. In 2008, there were 247,000,000 cases of malaria and almost 1,000,000 deaths from the disease
  19. 19. Ugi products have been tested to inhibit falcipain-2, an enzyme vital to plasmodium falciparum’s life cycle. </li></ul>(Ref: “Falcipain-2 inhibition results for 2 Ugi products.”, “Malaria Fact Sheet)<br /><ul><li>Find the solubility of a solute in a solvent at any temperature
  20. 20. At the solute’s melting point, the two are assumed miscible
  21. 21. During synthesis, benzalaniline was recrystallized in methanol. In order to extract the product, the mixture had to be cooled to precipitate in ethanol. The more substituted imine didn’t have to be cooled to form precipitate
  22. 22. Benzalaniline is more soluble at RT, but at 0°C is much less soluble</li></ul>The solubility increases with temperature in a logarithmic manner until the solvent’s boiling point<br />Source: World Health Organization, 2004<br />(Ref: “Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.”, “Synthesis of an imine from benzaldehyde and aniline.” , “Determination of solubility of sample 1A from UCExp262.” , “Determination of solubility of sample 1A from UCExp262 in toluene, acetonitrile, THF, and chloroform.”)<br />Attempts at Imine Synthesis<br />The solubility again increases, but plateaus at the solute’s miscibility point, which occurs at its melting point<br />Ugi Reaction and Imine Formation Mechanism<br /><ul><li>Continue to synthesize imines and investigate their solubility
  23. 23. When solubility for a solute in 5 different solvents is found, this information can be used to predict solubility in 72 solvents using the Abraham model
  24. 24. Test solubility predictions to refine the model
  25. 25. Apply the solubility information to optimize syntheses
  26. 26. An online web service “solvent selector” can be used to predict the optimal solvent to run a reaction in</li></ul>Benzalaniline was synthesized in methanol <br />Aniline and vanillin were reacted neat (no solvent)<br />(Ref: “Open Notebook Science Web Services.”)<br />4-chlorobenzaldehyde oxidation<br /><ul><li>Both reactions had been exposed to air and were washed with ethanol
  27. 27. MP of 227-230°C is consistent with impure 4-chlorobenzoic acid</li></ul>Both of these reactions formed some of the desired imine, but after a cold ethanol wash, there was very little imine remaining<br />Bradley, Jean-Claude and Lang, Andrew. “Open Notebook Science Web Services.” <http://onswebservices.wikispaces.com/><br />Curtin, Evan. “Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.” <http://usefulchem.wikispaces.com/Exp262><br />Curtin, Evan “Synthesis of an imine from benzaldehyde and aniline.” <http://usefulchem.wikispaces.com/Exp261><br />Curtin, Evan. “Determination of solubility of sample 1A from UCExp262.” <http://onschallenge.wikispaces.com/Exp206><br />Curtin, Evan. “Determination of solubility of sample 1A from UCExp262 in toluene, acetonitrile, THF, and chloroform.” <http://onschallenge.wikispaces.com/Exp207><br />Gut, Jiri. “Falcipain-2 inhibition results for 2 Ugi products.” < http://usefulchem.wikispaces.com/Exp165><br />“Malaria Fact Sheet.” World Heath Organization. 2004. <http://www.who.int/mediacentre/factsheets/fs094/en/index.html><br /><http://onswebservices.wikispaces.com/><br />Mirza, Khalid Baig. “Synthesis of compounds ranked 55-124 from library DEXP014-V2B” <http://usefulchem.wikispaces.com/Exp181><br />“Priority Environment and Health Risks.” World Health Organization. 2004. <http://www.who.int/heli/risks/en/><br />(Ref: “Synthesis of an imine from benzaldehyde and aniline.”<br />“Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.”)<br />(Ref: “Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.”)<br />

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