How to Synthesize Aspirin: Organic Chemistry Lab Procedure

The acetylation reaction follows a nucleophilic acyl substitution mechanism. The oxygen atom of the alcohol acts as a nucleophile and attacks one of the carbonyl carbons of acetic anhydride. Since acetic anhydride is symmetric, either carbonyl carbon can be attacked with equivalent results. The mechanism proceeds through proton transfer steps, ultimately forming the ester product (pentyl acetate) and acetic acid.

In nucleophilic acyl substitution, the nucleophilic amine attacks the electrophilic carbonyl carbon of acetic anhydride. This causes the carbonyl double bond to return and push electrons onto one of the oxygen atoms, which then leaves as an acetate ion. The remaining protonated amine deprotonates, yielding acetaminophen and acetic acid. This mechanism explains how the amine group becomes protected as an acetamide during the reaction.

The acetylation mechanism involves: (1) Pyridine attacks the carbonyl carbon of acetic anhydride, forming an acyl-pyridinium ion intermediate, (2) The alcohol attacks the carbonyl carbon of this intermediate, (3) The pyridine leaves with its electrons, (4) The protonated ester loses a proton to form the final ester. Pyridine acts as both nucleophile and base.

The synthesis of acetylsalicylic acid (aspirin) using acetic anhydride and salicylic acid with sulfuric acid as a catalyst follows a nucleophilic acyl substitution mechanism: sulfuric acid protonates the acetic anhydride, making it more electrophilic; the hydroxyl oxygen of salicylic acid then performs a nucleophilic attack on the electrophilic carbon, forming a tetrahedral intermediate; this intermediate undergoes intramolecular rearrangement to expel an acetate ion and form the acetyl-salicylic acid ester; finally, deprotonation occurs, regenerating the sulfuric acid catalyst and yielding the aspirin product.

Nucleophilic acyl substitution occurs through three distinct mechanisms: (1) Base-catalyzed mechanism with strong nucleophiles involves nucleophilic attack followed by leaving group departure in two steps; (2) Uncatalyzed mechanism with neutral nucleophiles requires an additional deprotonation step using a weak base like pyridine, totaling three steps; (3) Acid-catalyzed mechanism with weak nucleophiles (like water) requires six steps including carbonyl protonation, nucleophilic attack, deprotonation, leaving group protonation, departure, and final deprotonation to yield the carboxylic acid product.

The success of recrystallization depends critically on choosing the right solvent. The ideal solvent must have very low solubility for the solid at room temperature but very high solubility at elevated temperatures. This temperature-dependent solubility behavior is thermodynamically favorable because dissolution processes tend to become more favorable as temperature increases due to entropic considerations.

Recrystallization is a fundamental purification technique for solid compounds that converts amorphous solids (randomly arranged molecules with large intermolecular spaces containing impurities) into crystalline solids (ordered molecular arrangement with minimal spaces). The process relies on temperature-dependent solubility: compounds dissolve better at high temperatures and crystallize upon cooling. Two methods exist: cooling a saturated solution or evaporating solvent to increase concentration. Filtration techniques (hot filtration and vacuum filtration) separate crystals from impurities. Selecting the right solvent requires four criteria: temperature-dependent solubility (dissolves at high temperature, not at room temperature), impurity solubility (dissolves impurities at room temperature), chemical inertness (no reaction with compound), and volatility (easy evaporation). Ideal solvents are also non-flammable, non-toxic, and inexpensive. Practical solvent selection involves systematic testing: compounds that dissolve at both temperatures are unsuitable, while those that dissolve only at high temperature are ideal.

Recrystallization purifies solids by exploiting differential solubility. The process requires: (1) dissolving the impure compound in a hot solvent, (2) cooling to precipitate the pure compound, while impurities remain dissolved. Two critical solvent selection tests must be performed: at room temperature, the compound must precipitate (indicating low solubility), and at elevated temperature, it must dissolve completely (indicating high solubility). Water (H2O) has a bent molecular geometry due to lone pairs on oxygen, while pentane (C5H12) is a saturated hydrocarbon with only single bonds between carbon atoms.

Recrystallization is a fundamental purification method based on temperature-dependent solubility differences between desired compounds and impurities. Molecules are more soluble in solvents at higher temperatures and less soluble at lower temperatures. The process requires choosing a solvent where the desired compound has high solubility at elevated temperatures but low solubility at lower temperatures, while impurities either remain dissolved or precipitate after the desired compound. The method works best on reasonably pure materials (80%+). Success depends on proper solvent selection, which requires experience and understanding of solubility curves. The key limitation is that the desired molecule must be a solid.

Recrystallization is a purification technique for solids that exploits solubility differences. The solubility of any compound depends on three factors: the solute, the solvent, and the temperature. Solubility graphs plot temperature against solubility (grams per 100g water), showing how different compounds dissolve at various temperatures. A solution becomes saturated when the solubility limit is reached. For solids, solubility generally increases with temperature. When a saturated solution is cooled, it becomes supersaturated, causing the solute to crystallize out. This temperature-solubility relationship is the foundation of recrystallization, allowing controlled purification through temperature manipulation.

After experimental work, fume hood equipment must be properly returned: condensers go in their designated box with lid on, water circulation adapters are pushed toward the wall and returned to the locker. Hot plates must be unplugged and returned to the drawer, with aluminum equipment handled using gloves due to heat. Suction filtration apparatus belongs to the student and can be washed or put away dirty. The trap must be cleaned if chemicals accumulated. Clean glassware returns to the kit, while items like BNA flask and HSH funnel go to the locker. Bench and fume hood floor must be cleaned with acetone and paper towels. Before leaving, students must turn off air and vacuum flow, receive TA approval, lock their locker, and ensure the combination lock is secured.

This video provides essential safety protocols and equipment overview for Organic Chemistry Laboratory 1 at Technion's Faculty of Chemistry. Students must wear safety goggles, lab coats, closed-toe shoes, and long pants at all times, with long hair tied back. All work must be performed inside a fume hood, and chemical waste must be disposed of in special containers, never poured down the sink. Emergency procedures include using eye wash fountains for eye exposure, showers for body exposure, fire extinguishers and fire blankets for fires, and emergency stop switches for electrical incidents. Each student receives a locker containing standard glassware including beakers (50-400ml), Erlenmeyer flasks (50-250ml), funnels, graduated cylinders, condensers, and distillation apparatus. Before experiments, students must prepare a lab notebook, verify equipment condition, and thoroughly read and understand the procedure to avoid errors.

A fume hood is a self-contained environmental enclosure that evacuates volatile chemicals and provides physical protection through its sash; proper usage requires keeping the sash at an appropriate height to maintain adequate airflow, monitoring the airflow meter regularly, and activating the emergency purge function if backdraft occurs to increase airflow by three to four times the normal rate, ensuring safe containment of gases and protection from chemical reactions, fires, or explosions.

A chemical fume hood protects laboratory workers by capturing hazardous vapors through controlled airflow; proper operation requires maintaining the sash at 46 cm work height, keeping at least 25 cm distance from the front, avoiding obstruction of the rear air slot, using shelves to improve airflow, making slow direct movements, and minimizing foot traffic around the hood to prevent vapor escape.

This foundational segment covers essential laboratory skills including proper fume hood usage for capturing hazardous vapors, accurate liquid measurement using graduated cylinders with meniscus reading techniques, and safe handling of reactive chemicals. Students learn vacuum filtration setup using Buchner funnels, the critical importance of wetting filter paper to create tight seals, and proper technique for transferring hot solutions. The demonstration emphasizes safety protocols for exothermic reactions producing flammable gases like hydrogen, demonstrating how open-mouthed containers in fume hoods prevent dangerous pressure buildup. These fundamental skills form the basis for all subsequent chemical experiments.