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The Use of Non-Aqueous Solubility to Control Reaction Outcomes

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.

Abstract

Malaria

The Importance of Solubility Obtaining Solubility Data

Progress

What Comes Next?

References

Advisor: Professor Jean-Claude Bradley

Evan Curtin

Extrapolating RT Solubility and Melting Point

SAMS NMR Method for Determination of Solubility

Ugi Reaction and Imine Formation Mechanism

4-chlorobenzaldehyde oxidation

- Find the solubility of a solute in a solvent at any temperature- At the solute’s melting point, the two are assumed miscible- 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

- Benzalaniline is more soluble at RT, but at 0°C is much less soluble

Attempts at Imine Synthesis

Benzalaniline was synthesized in methanol

Aniline and vanillin were reacted neat (no solvent)

Both reactions had been exposed to air and were washed with ethanol

MP of 227-230°C is consistent with impure 4-chlorobenzoic acid

Both of these reactions formed some of the desired imine, but after a cold ethanol wash, there was very little imine remaining

SAMS = Semi Automated Measurement of Solubility Online web service created by Professor Bradley

(Drexel, Philadelphia, Pennsylvania) and Professor Andrew Lang (Oral Roberts University, Tulsa, Oklahoma)

Uses a Googledocs spreadsheet, available to the public Create a saturated solution of solute in a solvent Obtain HNMR spectra of the saturated solution Upload the spectra in JCAMP-dx format Specify solute and solvent peaks, and the number of

corresponding H’s Enter density and molar mass for the solute and solvent

(predicted densities from Chemspider.com are commonly used for solids)

Spreadsheet automatically calculates molarity

Life threatening disease caused by the parasite plasmodium falciparum

In 2008, there were 247,000,000 cases of malaria and almost 1,000,000 deaths from the disease

Ugi products have been tested to inhibit falcipain-2, an enzyme vital to plasmodium falciparum’s life cycle.

(Ref: “Falcipain-2 inhibition results for 2 Ugi products.”, “Malaria Fact Sheet)

Continue to synthesize imines and investigate their solubility

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

Test solubility predictions to refine the model Apply the solubility information to optimize syntheses An online web service “solvent selector” can be used

to predict the optimal solvent to run a reaction in

So far, 2 imines have been successfully synthesized

Solubility of benzalaniline in ethanol was found to be 1.3M

Solubility of N-Vanillylidene aniline was found in ethanol, toluene and acetonitrile (0.07M, 0.04M, and 0.08M, respectively)

Find a solvent in which the reactants are soluble and the products insoluble

Run the reaction Simply filter to get a

pure product No further workup is

needed, saves time

The solubility increases with temperature in a logarithmic manner until the solvent’s boiling point

The solubility again increases, but plateaus at the solute’s miscibility point, which occurs at its melting point

Creating a Saturated Solution

• To be certain that a solution is saturated, the solute must completely dissolve first, then precipitate out

• The supernatant will be saturated

1. Mix solute and solvent so that the solute doesn’t dissolve completely

2. Heat mixture until it equilibrates3. Decant if necessary4. Let cool to room temperature5. If no precipitate forms, blow air

onto solution to evaporate solvent6. Decant off the supernatant, which

will be saturated7. Smaller sample size is quicker to

equilibrate (done in 15 minutes)

ONSexp207: Solutions heated then cooled, 1,2,4 precipitated. Later used air to precipitate 3

Bradley, Jean-Claude and Lang, Andrew. “Open Notebook Science Web Services.” <http://onswebservices.wikispaces.com/>Curtin, Evan. “Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.” <http://usefulchem.wikispaces.com/Exp262>Curtin, Evan “Synthesis of an imine from benzaldehyde and aniline.” <http://usefulchem.wikispaces.com/Exp261>Curtin, Evan. “Determination of solubility of sample 1A from UCExp262.” <http://onschallenge.wikispaces.com/Exp206>Curtin, Evan. “Determination of solubility of sample 1A from UCExp262 in toluene, acetonitrile, THF, and chloroform.” <http://onschallenge.wikispaces.com/Exp207>Gut, Jiri. “Falcipain-2 inhibition results for 2 Ugi products.” < http://usefulchem.wikispaces.com/Exp165>“Malaria Fact Sheet.” World Heath Organization. 2004. <http://www.who.int/mediacentre/factsheets/fs094/en/index.html><http://onswebservices.wikispaces.com/>Mirza, Khalid Baig. “Synthesis of compounds ranked 55-124 from library DEXP014-V2B” <http://usefulchem.wikispaces.com/Exp181>“Priority Environment and Health Risks.” World Health Organization. 2004. <http://www.who.int/heli/risks/en/>

Source: World Health Organization, 2004

(Ref: “Synthesis of an imine from benzaldehyde and aniline.”“Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.”) (Ref: “Synthesis of four imines from vanillin, p-chlorobenzaldehyde, aniline and o-chloroaniline.”)

(Ref: “Open Notebook Science Web Services.”)

(Ref: “Open Notebook Science Web Services.”, “Determination of solubility of sample 1A from UCExp262 in toluene, acetonitrile, THF, and chloroform.” )

(Ref: “Synthesis of compounds ranked 55-124 from library DEXP014-V2B”)

(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.”)