This reaction is an example of a green synthesis of an organic compound. The new functional group yo — Organic Chemistry Chemistry Question

This reaction is an example of a green synthesis of an organic compound. The new functional group you will generate is important in many physiological processes as well as a crucial synthetic intermediate for a variety of drugs (e.g., Zetia® for lowering cholesterol, and Gleevec® and Taxol® for treating cancer). These three drugs alone grossed over $6 billion in 2006, the most recent year for which data were accessible.

The compounds you are making are traditionally synthesized in solvents such as dichloromethane or toluene over the course of many hours, often while boiling the reaction solution the entire time. In contrast, you are performing these same reactions using a benign solvent with reaction times of less than 15 min at room temperature. Our solvent, ethyl lactate (EL), is derived from renewable resources and is biodegradable. These reactions have been optimized previously by adjusting the polarity of the EL with water to attain the best combination of product quality and reaction speed. A few drops of lactic acid (LA), an acid found naturally in dairy products and in fatigued muscles, is used as a catalyst in some of the reactions.

Chemicals and Reagents
* Ethyl lactate
* Lactic acid
* Sodium chloride
* Substituted aniline (see below)
* Substituted aldehyde (see below)
* Ethanol
* Sodium tetrahydridoborate
* Methanol
* Hydrochloric acid (6 mol dm–3)
* Dichloromethane
* TLC solvent: 50 : 50 ethyl acetate/hexanes

[VISUAL]
Table of Suggested Aniline/Aldehyde Combinations and Composition of Solvent (Ethyl L^-Lactate : Water) Used for Reaction:
- p^-Anisidine (p-methoxyaniline) + p^-Nitrobenzaldehyde: 26 cm₃, 80% / use 23 cm₃ to dissolve the p-nitrobenzaldehyde
- p^-Bromoaniline + Salicylaldehyde: 5 cm₃, 80%
- p^-Bromoaniline + o^-Vanillin: 5 cm₃, 80%
- p^-Chloroaniline + p^-Nitrobenzaldehyde: 26 cm₃, 90% / use 23 cm₃ to dissolve the p-nitrobenzaldehyde
- p^-Ethoxyaniline (p-phenetidine) + p^-Nitrobenzaldehyde: 26 cm₃, 90% / use 23 cm₃ to dissolve the p-nitrobenzaldehyde
- p^-Fluoroaniline + Salicylaldehyde: 5 cm₃, 90%
- p^-Fluoroaniline + p^-Nitrobenzaldehyde: 26 cm₃, 80% with 2 drops lactic acid / use 23 cm₃ to dissolve the p-nitrobenzaldehyde
- p^-Iodoaniline + p^-Fluorobenzaldehyde: 5 cm₃, 80%
- p^-Iodoaniline + o^-Vanillin: 5 cm₃, 80% with 2 drops lactic acid
- p^-Toluidine + Salicylaldehyde: 5 cm₃, 80%
- p^-Toluidine + p^-(Dimethylamino)benzaldehyde: 8 cm₃, 80% with 2 drops lactic acid
- p^-Toluidine + p^-Nitrobenzaldehyde: 26 cm₃, 80% / use 23 cm₃ to dissolve the p-nitrobenzaldehyde

Equipment and Glassware
* Graduated cylinders, 10 cm₃ (2)
* Beral pipets (6)
* Beakers, 50 cm₃ (2)
* Hot plate
* Spatulas
* Buchner filter funnel with filter flask and filter paper
* Small flasks for recrystallization (2)
* Melting point apparatus and capillaries
* Small vials with caps (2)
* Vials with caps (preferably without liner), 20 cm₃ (2)
* UV lamps (optional)
* TLC spotters
* TLC plates (silica with fluorescent indicator A254)
* Chamber for TLC development
* Magnetic stirrer
* Ice water bath

Experimental Directions for Imine Preparation:
1. The reactants. Select a pair of reactants.
i. Calculate the mass corresponding to 0.010 mol for each of your compounds.
ii. Draw the structure of each compound and of the imine expected from this pair of reactants.
2. Begin chilling 50 cm₃ of brine (saturated aqueous NaCl) and 50 cm₃ of distilled water in an ice bath.
3. Reaction solvent. Find the proper solvent ratio for your reaction in the table of reactants above. Solvent ratios are expressed as % ethyl (L)-lactate in distilled water. The total volume of the solvent is 5.0 cm₃ unless otherwise specified. Measure the volumes of ethyl lactate and water in a graduated cylinder. If you need lactic acid (LA), add the indicated number of drops. Mix thoroughly.
4. Prepare your reactants. Label two 50-cm₃ beakers. Then, follow the set directions corresponding to the phases of your reactants. For the steps marked with an asterisk* check volumes in the table of reactants above.

If two solids:
Weigh the mass corresponding to 0.010 mol of the aniline directly into a labeled beaker; do the same for the aldehyde using a second labeled beaker.
*Add 2.0–2.5 cm₃ of your solvent to both beakers. Be certain to leave about 0.5–1.0 cm₃ solvent on reserve to use as a rinse.
Warm the beakers gently in the hood to dissolve both solids. This part should only take a few seconds. Mix thoroughly, and allow both solutions to cool to room temperature.

If one solid, one liquid:
Weigh the mass corresponding to 0.010 mmol of the aniline in a labeled beaker; do the same for the aldehyde using a second labeled beaker.
* Add 3.5 cm₃ of your solvent to the beaker containing the solid. Add 1.0 cm₃ solvent to the beaker containing the liquid. Leave the remaining 0.5 cm₃ solvent on reserve to use as a rinse. Mix thoroughly. Heat gently to dissolve the solid then allow the solution to cool to room temperature. Do not heat the liquid.

If two liquids:
Weigh the mass corresponding to 0.010 mol of the aniline directly into a labeled beaker; do the same for the aldehyde using a second labeled beaker.
Add 2.0–2.2 cm₃ of your solvent to both beakers. Be certain to leave about 0.6–1.0 cm₃ solvent on reserve to use as a rinse. Mix thoroughly. No heat is necessary.

5. Reaction. Do this next step as quickly as possible! Combine the solutions from two beakers and swirl a few times to mix. Some of the reactions are complete within seconds. Immediately use 0.5 cm₃ solvent to rinse the beakers and add the rinse to the reaction beaker. Quickly, swirl the solution in the beaker a few times to make sure it is completely homogeneous. All of step 5 should be completed in less than 5 s. Record the “combine” time.
6. Observe. Let the reaction mixture sit undisturbed for up to 15 min. Watch carefully, and record all observations. Note the exact time you see first crystals, and label this time as “begin crystallization”.
Once crystal formation appears to be complete, note the time again and label it as “end crystallization”. Record the color of the solid at this point.
Let the reaction sit undisturbed another 5 min. Note whether or not there is a color change (some reactions may become a lighter color, and you should indicate this). Then, put the reaction beaker in an ice bath for 5 min. Note the times.
7. Wash: Add 10 cm₃ of ice-cold brine to your solid. Use a clean spatula to transfer the solid gently in the brine until there are no solid chunks remaining. Some products are very compact, and you might need to scrape the surface of the solid gently to avoid chunks. You should end up with a suspension.
8. Vacuum filter this mixture.
9. Rinse and vacuum filter again: Rinse the beaker with 10 cm₃ of ice-cold distilled water and then pour this liquid evenly over the crystals in your Buchner funnel. This step will ensure that the surface of the crystals is rinsed of any compounds adhering to the surface of the crystals. Scrape any residue with a spatula and transfer it to the crystals in the Buchner funnel. Reconnect the vacuum hose to draw the liquid through the filter. Discard the filtrate into the waste container.
10. Recrystallize. Dry your crystals as well as possible on the filter, then recrystallize your crude product from ethanol or methanol to obtain a pure sample.
11. Weight and Determine the Melting Point: Allow the recrystallized product to dry as well as possible on the Buchner funnel and then obtain the melting point. Weigh your dried product.
12. Fluorescence (optional): Many of the imines have a beautiful fluorescence. To observe this, follow the procedure below:
a) Transfer pea-sized portions of your crude product into two small vials (with caps). Label one vial as “W” and the other as “HCl”.
b) Add two drops of distilled water to the small vial labeled “W”. Add two drops of HCl solution (6 mol dm–3) to the vial labeled “HCl”. Cap both vials tightly and allow the samples to sit undisturbed for at least 5 min. (The solids will not dissolve.) Note any color changes. Take the vials to a dark room. Turn your vials upside down and evaluate the fluorescence of both samples while the room is completely dark. The water containing vial will serve as the control for the acid-containing vial. Record your observations.
Long wave UV: use the UV lamp set to 365 nm.
Short wave UV: use the UV lamp set to 254 nm. Do not look into the UV lamp when it is on. It can damage your eyes.
Warning: Do not look into the UV lamp when it is on-it can damage your eyes.

Experimental Directions for Imine Reduction:
The toxicities of the imines and amines are unknown. In addition to goggles and a lab coat wear gloves throughout the experiment.

[VISUAL]

1. Yield and Stoichiometry: Based on the amount of imine to be used, calculate the theoretical yield of reduced product.
2. Prepare at least six TLC spotters. Store the spotters in a clean, dry beaker until you are ready to use them.
3. Prepare your imine TLC standard: Place about 0.05 g of your imine in a small vial. Dissolve in about 2 cm₃ of dichloromethane. Cap tightly to keep the solvent from evaporating.
4. Reduction and Workup:
a) Place approximately 0.8 – 1.0 g of your imine in a 20 cm₃ vial. Record the exact amount that you use.
b) Leave a small amount of imine in the original vial so that you can do color and melting point comparisons later.
c) Into a small vial weigh 0.2–0.3 g NaBH₄. Cap tightly.
d) Add 5 cm₃ methanol to the 20 cm₃ vial with your imine. Add a small magnetic stir bar to the vial, cap loosely and begin stirring. The sample will not dissolve but will form a suspension.
e) With a spatula, add about 1/5 of the NaBH₄ to the methanol suspension of the imine. Cap the vial LOOSELY. The reaction is exothermic; it is accompanied by evolution of hydrogen gas. Capping tightly could result in your vial exploding. Not capping at all can result in evaporation of methanol.
f) While waiting for the bubbling to end, perform TLC analysis of your imine standard. Spot a tiny amount at your start point, let the solvent evaporate, and then use the UV lamp at 254 nm to verify you have enough sample. Develop the plate in 50:50 ethyl acetate/hexanes. Afterward, visualize with the UV lamp. Calculate the Rf value.
g) After the bubbling subsides, add another 1/5 of the NaBH₄. Repeat this process until all of the NaBH₄ has been used. The whole process should take 10–15 minutes.
h) At some point during the addition steps, your imine will briefly dissolve and then a pale or white precipitate will immediately form. Record all of your observations.
i) Once the bubbling has completely stopped, do another TLC. This time, you will spot two lanes. One lane will contain a fresh aliquot of the imine standard used for the first TLC. The other lane will contain the product mixture, which you will prepare for TLC analysis as follows:
Use a Pasteur pipet to transfer 1–2 drops of the final suspension to a small vial. Dissolve this mixture in 1–2 cm₃ of dichloromethane. Use this solution to spot the plate. Again, use the UV lamp to verify you have enough sample spotted. Develop and visualize the plate as before. Once you have finished the TLC analysis, draw sketches of both plates in your report. Staple the plates on top of the corresponding pages that you hand in at the end of lab.
j) Add 10 cm₃ 5 % sodium bicarbonate to your reaction mixture. Mix thoroughly and filter the resulting solid.
k) Once all solid has been transferred to the filter paper, rinse the solid with 10 cm₃ of cold distilled water. Allow the sample to air dry. You might want to recrystallize the product from methanol.
5. Analysis of the Reduction Product:
a) Obtain the melting point. Some of the melting points may be rather high.
b) If possible, obtain ¹H and ¹³C NMR spectra.