Comprehensive Study Guide for Pharmaceutical and Medicinal Organic Chemistry Laboratory

Stoichiometry and Chemical Reaction Yields

• Stoichiometry is the branch of chemistry concerned with the quantitative relationships between reactants and products in a chemical reaction.
• It is founded on the law of conservation of mass, which states that the total mass of the reactants must equal the total mass of the products. Consequently, the quantitative relations among reactants and products form ratios of positive integers. Knowing the quantity of separate reactants allows for the theoretical calculation of product amounts, and conversely, determining the yield of a product allows empirical determination of required reactant amounts.
• The systematic process for solving stoichiometric problems follows five sequential steps:
  1. Balance the chemical equation.
  2. Identify the limiting reagent.
  3. Calculate the theoretical yield.
  4. Determine the actual yield through experimental execution.
  5. Calculate the percentage yield.
• A limiting reactant (or limiting reagent) is the substance in a chemical reaction that is completely consumed first, thereby limiting the maximum amount of product that can be formed. Once the limiting reactant is exhausted, the reaction halts.
• An excess reactant is the reactant that remains unreacted after the limiting reactant has been entirely consumed.
• An everyday analogy illustrates this concept: combining car bodies and tires to assemble complete vehicles.

• In this car assembly process, $8$ car bodies plus $48$ tires are available. Since each car requires exactly $4$ tires, $8$ cars require $32$ tires. Thus, $8$ complete cars are assembled, leaving $16$ tires in excess. Regardless of the surplus of tires, no additional cars can be manufactured because car bodies serve as the limiting component.
• In laboratory chemistry, real-world reactions rarely produce $100\text{\%}$ of the theoretical quantity written on paper. Product loss occurs due to experimental errors, incomplete reactions, side reactions, transfer losses, and impurities.
• The success and efficiency of a chemical reaction are evaluated using the percentage yield, which is defined as the ratio of actual yield to theoretical yield multiplied by $100\text{\%}$:   $\text{Percentage Yield} = \left( \frac{\text{Actual Yield}}{\text{Theoretical Yield}} \right) \times 100$
• Theoretical yield represents the maximum mass of product calculated stoichiometrically from the complete consumption of the limiting reagent.
• Actual yield represents the mass of product physically isolated from the experiment in the laboratory.

Stoichiometric Calculation Examples

• Practice balancing basic chemical equations:
  • Aluminium and Chlorine: $2\text{Al} + 3\text{Cl}_2 \rightarrow 2\text{AlCl}_3$
  • Barium Chloride and Aluminium Sulfate: $3\text{BaCl}_2 + \text{Al}_2(\text{SO}_4)_3 \rightarrow 3\text{BaSO}_4 + 2\text{AlCl}_3$
  • Propane Combustion: $C_3H_8 + 5O_2 \rightarrow 3CO_2 + 4H_2O$
  • Methylamine Combustion: $4CH_3NH_2 + 9O_2 \rightarrow 4CO_2 + 10H_2O + 2N_2$
  • Benzene Combustion: $2C_6H_6 + 15O_2 \rightarrow 12CO_2 + 6H_2O$
• Problem 1: Combustion of Ethylene ($C_2H_4$)
  • Reaction statement: $4.95\,g$ of ethylene ($C_2H_4$) is reacted with $3.25\,g$ of oxygen ($O_2$).
  • Step 1: Balance the chemical equation:     $C_2H_4 + 3O_2 \rightarrow 2CO_2 + 2H_2O$
  • Step 2: Determine molar masses:
  • Molar mass of $C_2H_4$: $(12\,g\,mol^{-1} \times 2) + (1\,g\,mol^{-1} \times 4) = 28\,g\,mol^{-1}$
  • Molar mass of $O_2$: $16\,g\,mol^{-1} \times 2 = 32\,g\,mol^{-1}$
  • Molar mass of $CO_2$: $(12\,g\,mol^{-1} \times 1) + (16\,g\,mol^{-1} \times 2) = 44\,g\,mol^{-1}$
  • Step 3: Calculate potential yield of $CO_2$ from each reactant:
  • From $C_2H_4$:       $4.95\,g\,C_2H_4 \times \frac{1\,mol\,C_2H_4}{28\,g\,C_2H_4} \times \frac{2\,mol\,CO_2}{1\,mol\,C_2H_4} \times \frac{44\,g\,CO_2}{1\,mol\,CO_2} = 15.557\,g\,CO_2$
  • From $O_2$:       $3.25\,g\,O_2 \times \frac{1\,mol\,O_2}{32\,g\,O_2} \times \frac{2\,mol\,CO_2}{3\,mol\,O_2} \times \frac{44\,g\,CO_2}{1\,mol\,CO_2} = 2.979\,g\,CO_2$
  • Step 4: Identify limiting reagent and theoretical yield:
  • Oxygen ($O_2$) is the limiting reactant because it produces the smaller amount of product ($2.98\,g$ or rounded to $2\,g$).
  • Theoretical yield of $CO_2$ is $2\,g$ (or $2.98\,g$ exact).
• Problem 2: Burning Propane ($C_3H_8$) in Excess Oxygen
  • Reaction statement: $12\,g$ of propane ($C_3H_8$) is burned in excess oxygen. Determine grams of water ($H_2O$) produced.
  • Step 1: Balance equation:     $C_3H_8 + 5O_2 \rightarrow 3CO_2 + 4H_2O$
  • Step 2: Determine molar masses:
  • Molar mass of $C_3H_8$: $(12 \times 3) + (1 \times 8) = 44\,g\,mol^{-1}$
  • Molar mass of $H_2O$: $(1 \times 2) + (16 \times 1) = 18\,g\,mol^{-1}$
  • Step 3: Dimensional analysis:     $12\,g\,C_3H_8 \times \frac{1\,mol\,C_3H_8}{44\,g\,C_3H_8} \times \frac{4\,mol\,H_2O}{1\,mol\,C_3H_8} \times \frac{18\,g\,H_2O}{1\,mol\,H_2O} = 19.636\,g\,H_2O$
  • Yield of $H_2O$ is approximately $19\,g$ (or $19.64\,g$).
• Problem 3: Synthesis of Acetylsalicylic Acid (Aspirin/ASA)
  • Reaction statement: $5\,g$ of salicylic acid reacts with $10\,mL$ of acetic anhydride. Determine mass of acetylsalicylic acid (ASA) produced.
  • Chemical equation:     $C_7H_6O_3 + C_4H_6O_3 \rightarrow C_9H_8O_4 + C_2H_4O_2$

• Molar masses:
  • Salicylic Acid ($C_7H_6O_3$): $(12 \times 7) + (1 \times 6) + (16 \times 3) = 138\,g\,mol^{-1}$
  • Acetic Anhydride ($C_4H_6O_3$): $(12 \times 4) + (1 \times 6) + (16 \times 3) = 102\,g\,mol^{-1}$
  • Acetylsalicylic Acid ($C_9H_8O_4$): $(12 \times 9) + (1 \times 8) + (16 \times 4) = 180\,g\,mol^{-1}$
• Calculations:
  • From Salicylic Acid ($SA$):       $5\,g\,SA \times \frac{1\,mol\,SA}{138\,g\,SA} \times \frac{1\,mol\,ASA}{1\,mol\,SA} \times \frac{180\,g\,ASA}{1\,mol\,ASA} = 6.52\,g\,ASA$
  • From Acetic Anhydride ($AA$) (density of $AA = 1.08\,g/mL$):       $\text{Mass of } AA = 10\,mL \times 1.08\,g/mL = 10.8\,g\,AA$$10.8\,g\,AA \times \frac{1\,mol\,AA}{102\,g\,AA} \times \frac{1\,mol\,ASA}{1\,mol\,AA} \times \frac{180\,g\,ASA}{1\,mol\,ASA} = 19.06\,g\,ASA$
• Salicylic acid yields the smaller quantity ($6.52\,g$ or rounded to $6\,g$), making it the limiting reactant. The theoretical yield of aspirin is $6.52\,g$.
  • Problem 4: Aspartame Hydrolysis
• Reaction statement: $378\,g$ of aspartame ($C_{14}H_{18}N_2O_5$) reacts with water to form aspartic acid ($C_4H_7NO_4$), methanol ($CH_3OH$), and phenylalanine ($C_9H_{11}NO_2$).
• Balanced equation:     $C_{14}H_{18}N_2O_5 + 2H_2O \rightarrow C_4H_7NO_4 + CH_3OH + C_9H_{11}NO_2$
• Molar masses:
  • Aspartame ($C_{14}H_{18}N_2O_5$): $(12 \times 14) + (1 \times 18) + (14 \times 2) + (16 \times 5) = 294\,g\,mol^{-1}$
  • Phenylalanine ($C_9H_{11}NO_2$): $(12 \times 9) + (1 \times 11) + (14 \times 1) + (16 \times 2) = 165\,g\,mol^{-1}$
• Theoretical yield of phenylalanine:     $378\,g\,\text{Aspartame} \times \frac{1\,mol\,\text{Aspartame}}{294\,g\,\text{Aspartame}} \times \frac{1\,mol\,\text{Phenylalanine}}{1\,mol\,\text{Aspartame}} \times \frac{165\,g\,\text{Phenylalanine}}{1\,mol\,\text{Phenylalanine}} = 212.14\,g$
• Percentage yield calculation if actual yield is $150\,g$:     $\text{Percentage Yield} = \frac{150\,g}{212.14\,g} \times 100 = 70.71\text{\%}$

Alcohols: Classification, Reactions, and Identification

• Alcohols are organic compounds containing a hydroxyl group ($-OH$) covalently bonded to a saturated, $sp^3$-hybridized carbon atom ($R\text{-}OH$).
• Hydroxyl groups can be attached to alkanes, alkenes, or alkynes. When a hydroxyl group is attached directly to an aromatic benzene ring, the compound is called a phenol.
• Phenol is structurally considered an enol, defined as an alkene carbon directly bonded to a hydroxyl group ($C=C\text{-}OH$).
• Classification by the number of hydroxyl groups:
  • Monohydric alcohol: Contains exactly $1$ hydroxyl group. Example: Propanol ($C_3H_7OH$).
  • Dihydric alcohol: Contains $2$ hydroxyl groups. Example: 1,2-Ethanediol ($CH_2OH\text{-}CH_2OH$).

• Trihydric alcohol: Contains $3$ hydroxyl groups. Example: 1,2,3-Propanetriol (Glycerol).

• Classification by the degree of substitution of the carbinol carbon:
  • Primary alcohol ($1^\circ$): The carbon bearing the $-OH$ group is bonded to only one other carbon atom and has $2$ available hydrogen atoms.
  • Secondary alcohol ($2^\circ$): The carbon bearing the $-OH$ group is bonded to two other carbon atoms and has $1$ available hydrogen atom.

• Tertiary alcohol ($3^\circ$): The carbon bearing the $-OH$ group is bonded to three other carbon atoms and has $0$ available hydrogen atoms on the carbinol carbon.

• Reactions of Alcohols: Oxidation
  • Primary Alcohols ($RCH_2OH$): Oxidized first to an aldehyde ($RCHO$), which can undergo further oxidation to a carboxylic acid ($RCOOH$).
  • Mild oxidizing reagents like Dess-Martin periodinane or Pyridinium Chlorochromate (PCC) stop the oxidation at the aldehyde stage.
  • Strong oxidizing reagents such as Chromic acid ($CrO_3$), Sodium dichromate ($Na_2Cr_2O_7$), or Potassium permanganate ($KMnO_4$) convert primary alcohols directly to carboxylic acids.
  • Oxidation involves removing two hydrogen atoms (one from $-OH$, one from carbon) to form a $C=O$ double bond.
  • Secondary Alcohols ($R_2CHOH$): Oxidized to ketones ($RC=OR$) upon treatment with oxidizing agents.

- Ketones cannot be easily oxidized further because no hydrogen remains on the carbonyl carbon.
- The smallest ketone is Propanone (Acetone, $CH_3COCH_3$), requiring at least $3$ carbon atoms.

• Tertiary Alcohols ($R_3COH$): Resist oxidation under standard conditions because there is no hydrogen atom on the carbinol carbon. Treatment with oxidizing reagents yields no reaction.

• Reactions of Alcohols: Elimination (Dehydration)
  • Dehydration of alcohol to Alkene: Heating an alcohol at $170\,^\circ\text{C}$ in the presence of concentrated sulfuric acid ($H_2SO_4$) removes water ($-OH$ from carbinol carbon, $-H$ from adjacent carbon) to form a carbon-carbon double bond (alkene). Reversible via hydration.
  • Dehydration of excess alcohol to Ether: Heating excess alcohol at $145\,^\circ\text{C}$ with concentrated $H_2SO_4$ condenses two alcohol molecules, eliminating water to produce an ether ($R\text{-}O\text{-}R$).

• Reactions of Alcohols: Substitution
  • Substitution converts the $-OH$ group of an alcohol into a halogen using hydrohalic acids ($HX$, where $X = Cl, Br, I, F$; Astatine is synthetic and excluded) under heat, forming an alkyl halide and water.

• Diagnostic Tests for Alcohols:
  • Ferric Chloride Test ($FeCl_3$) for Enol/Phenolic Structure:
  • Ferric chloride solution (yellow/orange) reacts specifically with compounds containing an enol structure ($C=C\text{-}OH$) or phenolic ring to produce a distinct purple, violet, blue, or dark-colored iron complex.
  • Compounds undergo keto-enol tautomerism, interconverting between carbonyl and enol forms.

- Experimental observations with Ferric Chloride:
  - N-butyl alcohol (Butan-1-ol): Remains yellow (negative, no enol/double bond).
  - Ethanol: Remains yellow (negative).
  - Glycerol: Remains yellow (negative).
  - Benzyl alcohol: Remains yellow (negative; $-OH$ is attached to an $sp^3$ carbon, not directly to the benzene ring).
  - Phenol: Turns purple/violet (positive enol structure; $-OH$ attached directly to aromatic double bond).

• Permanganate Oxidation Rate Test:
  • Potassium permanganate ($KMnO_4$) oxidizes primary and secondary alcohols in basic ($NaOH$) or acidic ($6.0\,N\,H_2SO_4$) media.
  • Reaction rate: Primary alcohols react fastest, followed by secondary alcohols. Tertiary alcohols do not react.

- In permanganate oxidation, purple $KMnO_4$ ($Mn^{VII}$) is reduced to manganese dioxide ($MnO_2$), which forms a distinct brown precipitate.

Aldehydes and Ketones: Properties, Reactions, and Chemical Tests

• Aldehydes and ketones are the two simplest families of carbonyl-containing compounds ($C=O$).
  • Aldehydes ($RCHO$) have at least one hydrogen atom attached to the carbonyl carbon.
  • Ketones ($RCOR'$) have two carbon groups attached to the carbonyl carbon.
• Natural occurrence and aromas:
  • Aldehydes provide natural flavors like cinnamon, vanilla, and almond.
  • Ketones yield natural fragrances like jasmone (from jasmine flowers) and muscone (from male musk deer).
• Physical Properties:
  • Both are moderately polar compounds due to the polar carbonyl group.
  • Boiling points: Higher than nonpolar alkanes of comparable molecular weight, but lower than alcohols because aldehydes and ketones cannot form intermolecular hydrogen bonds with themselves.
  • State: Lower molecular weight aldehydes and ketones are liquids; those with more than $12$ carbon atoms are solids.
  • Solubility: Soluble in organic solvents. Compounds with fewer than $5$ carbons are water-soluble. Ketones serve as versatile solvents for both polar and nonpolar substances. As carbon chain length increases, lipophilicity increases and water solubility decreases.
  • Flammability: Low-boiling aldehydes and ketones are highly flammable.
  • Toxicity: Simple ketones generally exhibit low toxicity; simple aldehydes (especially formaldehyde) are toxic.
  • Monosaccharides are classified as aldoses (containing an aldehyde) or ketoses (containing a ketone).
• Chemical Preparation and Oxidation Reactions:
  • Oxidation of primary alcohols with PCC yields aldehydes.

• Oxidation of secondary alcohols yields ketones.

• Aldehydes are easily oxidized to carboxylic acids because of the hydrogen attached to the carbonyl carbon. Mild oxidizing agents, including atmospheric oxygen, can cause this conversion (aldehydes are stored under inert nitrogen gas to prevent auto-oxidation).

• Ketones lack a hydrogen atom on the carbonyl carbon and are completely resistant to mild oxidation.

• Hydration of terminal alkynes: Hydration of a terminal alkyne with sulfuric acid and mercuric sulfate ($HgSO_4$) yields a methyl ketone. Hydroboration-oxidation yields an aldehyde.
  • Diagnostic Tests to Distinguish Aldehydes from Ketones:
• Tollen's Test (Silver Mirror Test):
  • Tollen's reagent contains the diammine silver(I) complex ion, $[Ag(NH_3)_2]^+$ in aqueous ammonia.
  • Aldehydes reduce $Ag^+$ to metallic silver, coating the inner test tube wall with a shiny silver mirror or creating a grey precipitate.
  • Ketones give no reaction; the solution remains clear and colorless.
• Benedict's Test:
  • Benedict's reagent contains copper(II) ions ($Cu^{2+}$) complexed with citrate ions in sodium carbonate solution (blue color).
  • Aldehydes reduce blue $Cu^{2+}$ (cupric) to red $Cu^+$ (cuprous), forming a brick-red precipitate of copper(I) oxide ($Cu_2O$).
  • Ketones give no reaction; the solution remains blue.

Carboxylic Acids and Esters: Reactions, Identification, and AHAs

• Carboxylic acids ($RCOOH$) contain a carboxyl group ($-COOH$). Derivatives include esters ($RCOOR'$) and amides ($RCONR'R''$).
• Chemical Reactions of Carboxylic Acids:
  1. Neutralization with Base: Acid + Base $\rightarrow$ Carboxylate Salt + Water.      $\text{Carboxylic Acid} + \text{Strong Base } (NaOH) \rightarrow \text{Carboxylic Acid Salt} + H_2O$

 - Propionic acid + $NaOH \rightarrow$ Sodium propanoate + $H_2O$.
 - Hex-2,4-dienoic acid + $KOH \rightarrow$ Potassium hex-2,4-dienoate + $H_2O$.

2. Reaction with Thionyl Chloride ($SOCl_2$): Converts carboxylic acid to acid chloride (acyl chloride), generating $HCl$ and $SO_2$ gases.

3. Esterification: Acid + Alcohol $\rightleftharpoons$ Ester + Water (in the presence of $H_2SO_4$).
4. Amidation: Acid + Amine $\rightleftharpoons$ Amide + Water.
5. Reduction: Carboxylic acids are reduced back to primary alcohols using powerful reducing agents like Lithium Aluminium Hydride ($LiAlH_4$).

• Esterification Procedure and Fragrance Compounds:
  • Warming acetic acid ($CH_3COOH$) with ethanol ($CH_3CH_2OH$) and concentrated $H_2SO_4$ produces Ethyl Acetate ($CH_3COOCH_2CH_3$), characterized by a fruity, nail-polish remover, or plastic balloon odor.

• Reaction of Methanol with Salicylic acid produces Methyl Salicylate (Oil of Wintergreen), which exhibits a minty odor.

• Characteristic ester odors:
  • Iso-butyl formate: Raspberry
  • Butyl acetate: Apple

- Ethyl butyrate: Pineapple

- Propyl isobutyrate: Rum
- Benzyl acetate: Peach

- Octyl acetate: Orange

- Methyl phenylacetate: Honey

- Ethyl methylphenylglycidate: Strawberry

• Oxidation Resistance and Alpha-Hydroxy Acids (AHAs):
  • Carboxylic acids resist oxidation. However, Alpha-Hydroxy Acids (AHAs)—acids bearing a hydroxyl group on the alpha carbon adjacent to the carbonyl carbon—can be oxidized by $KMnO_4$.
  • Common cosmetic AHAs include Lactic acid (2-hydroxypropanoic acid), Glycolic acid, Citric acid, Tartaric acid, and Mandelic acid.

• Esters and Hydrolysis:
  • Esters lack hydroxyl hydrogens, preventing self-hydrogen bonding, so they have lower boiling points than parent carboxylic acids.
  • Acetic acid BP: $118\,^\circ\text{C}$
  • Methyl acetate BP: $57\,^\circ\text{C}$
  • Ethyl acetate BP: $77\,^\circ\text{C}$
  • Hydrolysis is the cleavage of bonds by water addition:
  • Acid-catalyzed hydrolysis: Reverse of esterification.

- Base-catalyzed hydrolysis (Saponification): Ester + Base ($NaOH$/$KOH$) $\rightarrow$ Carboxylate Salt + Alcohol.

• Aspirin Ester Hydrolysis Test:
  • Acetylsalicylic acid (ASA) heated with water and $HCl$ hydrolyzes into salicylic acid and acetic acid.

- Addition of $FeCl_3$ turns the solution purple/violet due to liberated salicylic acid ( phenolic enol structure).

Synthesis and Clinical Pharmacokinetics of Ethanol

• Ethanol properties:
  • Chemical formula: $CH_3CH_2OH$ (Molar mass = $46\,g\,mol^{-1}$).
  • Synonyms: Absolute alcohol, grain alcohol, hydroxyethane, methylcarbinol, ethyl hydrate.
  • Volatile, flammable, colorless liquid; BP = $78\,^\circ\text{C}$ ($351\,K$ / $172\,^\circ\text{F}$).
  • Completely miscible with water and organic solvents due to hydrogen bonding; highly hygroscopic.

• Alcohol content in commercial beverages:
  • Beer: $3\text{-}5\text{\%}$ alcohol by volume ($12\,fl\,oz$ regular beer).
  • Malt liquor: $7\text{\%}$ alcohol ($8\text{-}9\,fl\,oz$).
  • Table wine: $10\text{-}13\text{\%}$ alcohol ($5\,fl\,oz$).
  • Distilled spirits (hard liquor): $35\text{-}90\text{\%}$ alcohol ($1.5\,fl\,oz$ shot of $80$-proof).
  • Proof scale: Proof value is exactly twice the alcohol percentage by volume ($40\text{\%}$ alcohol = $80$-proof).

• Industrial and Medical Uses:
  • Non-beverage ethanol is denatured by adding toxic/unpalatable substances like methanol, camphor, kerosene, or benzene.
  • Gasohol: Blend of $1$ part ethanol and $9$ parts gasoline.
  • Solvent in paints, varnishes, tinctures, and elixirs.
  • Used as fluid in thermometers, preservative for biological specimens ($20\text{\%}$ solution in ophthalmology), and CNS depressant.
• Blood Alcohol Concentration (BAC) and Physiological Effects:
  • Measured in $g/dL$ or $mg/dL$ ($0.08\text{\%} = 0.08\,g/dL = 80\,mg/dL$).
  • Physiological Scale:
  • $0.02\,g/dL$ ($20\,mg/dL$): Relaxation, slight reaction time slowing.
  • $0.05\,g/dL$ ($50\,mg/dL$): Euphoria, impaired judgment/reasoning. Legal limit in the Philippines for private motorists.
  • $0.00\,g/dL$: Mandatory legal limit in the Philippines for drivers of public utility vehicles, trucks, buses, and motorcycles.
  • $0.08\,g/dL$ ($80\,mg/dL$): Legal intoxication threshold in the US. Loss of balance and coordination.
  • $0.10\,g/dL$ ($100\,mg/dL$): Slurred speech, motor impairment.
  • $0.15\text{-}0.24\,g/dL$: Blackout risk, severe nausea, stumbling.
  • $0.25\text{-}0.35\,g/dL$: Inability to walk, loss of consciousness.
  • $0.40\text{-}0.45\,g/dL$: High risk of coma and respiratory death.
  • $> 0.60\,g/dL$: Loss of spontaneous respiration and cardiovascular regulation leading to death.

• Physiological Mechanism and Metabolism:
  • In the pituitary gland, ethanol inhibits vasopressin (antidiuretic hormone, ADH), causing diuresis and dehydration.
  • In the stomach, ethanol stimulates gastric acid secretion.
  • Peripheral vasodilation causes skin flushing and heat loss.
  • Hepatic Metabolic Pathway:     $\text{Ethanol } (CH_3CH_2OH) \xrightarrow{\text{Alcohol Dehydrogenase}} \text{Acetaldehyde } (CH_3CHO) \xrightarrow{\text{Aldehyde Dehydrogenase}} \text{Acetic Acid } (CH_3COOH)$
  • Alcohol Dehydrogenase is inhibited by Fomepizole (used for ethanol/methanol toxicity).
  • Aldehyde Dehydrogenase is irreversibly inhibited by Disulfiram (Antabuse), causing accumulation of toxic acetaldehyde during alcohol withdrawal therapy.

• Breathalyzer Test: Measures ethanol in expired air via oxidation by bright yellow-orange Potassium Dichromate ($K_2Cr_2O_7$), which is reduced to blue-green Chromium(III) ($Cr^{3+}$).
• Drug Interactions: Intensifies CNS depression from barbiturates, benzodiazepines, opioids, phenothiazines, and antidepressants.
• Toxicity: Classified as a teratogen causing Fetal Alcohol Syndrome. Chronic intake causes elevated serum triglycerides and liver cirrhosis through acetaldehyde-induced lipid peroxidation.
  • Ethanol Synthesis Methods:
• Industrial Addition (Ethylene Hydration): Ethene + Steam $\rightarrow$ Ethanol.
• Fermentation of Sucrose:
  • Yeast enzymes:
    • Invertase hydrolyzes sucrose ($C_{12}H_{22}O_{11}$, MW = 342) into glucose and fructose ($C_6H_{12}O_6$, MW = 180).

   - Zymase ferments glucose into ethanol and carbon dioxide:

         $C_6H_{12}O_6 \xrightarrow{\text{Zymase}} 2CH_3CH_2OH + 2CO_2$ - Fermentation occurs over $3$ days at $25\text{-}30\,^\circ\text{C}$, followed by fractional distillation.

• Laboratory Distillation Procedure:
  • Distillation separates liquids based on boiling points ($79\,^\circ\text{C}$ for ethanol vs $100\,^\circ\text{C}$ for water).
  • The setup consists of a heat source, distilling flask containing fermented mixture and boiling chips (to prevent bumping), cork, thermometer, water-jacketed condenser (water enters at the bottom, exits at the top), adapter, and receiving flask.

• Stoichiometric Calculation for Fermentation:
  • From $12\,g$ sucrose ($12\text{\%}\,w/v$ solution in $100\,mL$):     $12\,g\,\text{Sucrose} \times \frac{1\,mol\,\text{Sucrose}}{342\,g} \times \frac{1\,mol\,\text{Glucose}}{1\,mol\,\text{Sucrose}} \times \frac{180\,g}{1\,mol\,\text{Glucose}} = 6.32\,g\,\text{Glucose}$$6.32\,g\,\text{Glucose} \times \frac{1\,mol\,\text{Glucose}}{180\,g} \times \frac{2\,mol\,\text{Ethanol}}{1\,mol\,\text{Glucose}} \times \frac{46\,g}{1\,mol\,\text{Ethanol}} = 3.23\,g\,\text{Ethanol}$
  • Theoretical yield = $3.23\,g$ ethanol. If actual yield = $2\,g$, the percentage yield is:     $\text{Percentage Yield} = \frac{2\,g}{3.23\,g} \times 100 = 61.92\text{\%}$

• Chemical Identification Tests for Ethanol:
  • Combustion Test: Burns with a pale blue, non-luminous flame yielding $CO_2$ and water vapor.
  • Iodoform Test: Forms a yellow precipitate in the presence of iodine and base.
  • Esterification Test: Reacts with acetic acid to yield ethyl acetate, recognized by a plastic balloon/nail polish odor.
• Antiseptic Activity Trends:
  • Antiseptic potency increases with carbon chain length up to $8$ carbons (octanol). Above $9$ carbons, cell membrane penetration fails, causing loss of activity.
  • Branching decreases antiseptic activity, except in isopropyl alcohol.
  • Methanol toxicity: Converted by the liver to formic acid (methanoic acid), which destroys the optic nerve, causing irreversible blindness.

Synthesis, Uses, and Metabolism of Benzoic Acid

• Benzoic acid properties:
  • Chemical formula: $C_6H_5COOH$ (Molar mass = $122\,g\,mol^{-1}$).
  • IUPAC name: Phenylcarboxylic acid. Synonyms: Benzenemethanoic acid, carboxybenzene, benzeneformic acid, dracylic acid, flowers of Benjamin.
  • White crystalline solid, slightly soluble in cold water ($0.29\,g/100\,mL$), soluble in ethanol, slightly soluble in benzene and acetone.

• Applications:
  • Industrial: Solvents, dye carriers, disinfectants, additives, penetrants, pesticides.
  • Food Preservative: Inhibits mold, yeast, and bacteria at concentrations of $0.05\text{-}0.1\text{\%}$. Effective in acidic media ($pH < 5$). Preserves carbonated beverages, fruit juices, pickles. Sodium Benzoate is designated by international additive code E211.
  • Pharmaceutical & Medical:
  • Whitfield's Ointment: Active antifungal formulation combining $6\text{\%}$ Benzoic Acid and $3\text{\%}$ Salicylic Acid for tinea, ringworm, and athlete's foot.

- Friar's Balsam (Compound Benzoin Tincture USP): Topical antiseptic and inhalant decongestant containing benzoin resin, storax, and Cape aloes.

• Synthesis Methods:
  1. Acid-catalyzed Ester Hydrolysis: Hydrolysis of Ethyl Benzoate with $H_2SO_4$ yields benzoic acid and ethanol.
  2. Partial Oxidation of Toluene: Toluene is oxidized by oxygen using cobalt or manganese naphthenate catalysts via benzylic hydroxylation to benzyl alcohol, then benzaldehyde, and finally benzoic acid.

3. Oxidation of Benzaldehyde with $KMnO_4$:      $3C_6H_5CHO + 2KMnO_4 + HCl \rightarrow 3C_6H_5COOH + 2MnO_2 + KOH + KCl$

 - Experimental procedure: $2\,mL$ benzaldehyde ($d = 1.0415\,g/mL$, MW = 106) is mixed with water and $NaOH$, heated under reflux condenser, and $105\,mL$ $KMnO_4$ is added dropwise over $15\text{-}20$ minutes. Brown $MnO_2$ precipitate is filtered out. Methanol acts as a decolorizer. Filtrate is acidified with concentrated $HCl$ and cooled in an ice bath to precipitate benzoic acid crystals.

• Stoichiometric Calculation:
  • Mass of benzaldehyde reactant:     $2\,mL \times 1.0415\,g/mL = 2.083\,g\,\text{Benzaldehyde}$
  • Molar conversions:     $2.083\,g\,\text{Benzaldehyde} \times \frac{1\,mol\,\text{Benzaldehyde}}{106\,g} \times \frac{3\,mol\,\text{Benzoic Acid}}{3\,mol\,\text{Benzaldehyde}} \times \frac{122\,g}{1\,mol\,\text{Benzoic Acid}} = 2.397\,g$
  • Theoretical yield = $2.40\,g$ Benzoic acid.
  • Percentage yield if actual isolated mass is $0.5\,g$:     $\text{Percentage Yield} = \frac{0.5\,g}{2.40\,g} \times 100 = 20.83\text{\%}$

• Diagnostic Tests and Metabolism:
  • Ester Formation: Reacting benzoic acid with n-propyl alcohol and $H_2SO_4$ forms Propyl Benzoate, which displays a balsamic, fruity, nut-like odor.

• Solubility Test: Insoluble in cold water; dissolves readily in $10\text{\%}\,NaOH$ by forming soluble sodium benzoate salt ($C_6H_5COO^-Na^+$).
• Carboxylate Salt Uses:
  • Sodium benzoate: Preservative.
  • Calcium & Sodium propanoate: Mold inhibitors (calcium propionate at $0.33\text{\%}$ extends bread shelf life from $7$ to $14$ days).
  • Zinc undecylenate: Topical fungicide (Derman cream).

- Aluminum acetate: Astringent.

• Hepatic Metabolism: Benzoic acid undergoes amino acid conjugation with glycine as its primary metabolic pathway, forming Hippuric Acid, which is excreted in urine. Secondary conjugation with glucuronic acid forms benzyl glucuronide.

Synthesis, Pharmacodynamics, and Toxicology of Acetylsalicylic Acid (Aspirin)

• Acetylsalicylic Acid (ASA / Aspirin) properties:
  • Chemical formula: $C_9H_8O_4$ (Molar mass = $180\,g\,mol^{-1}$).
  • IUPAC name: 2-acetoxybenzoic acid. Synonyms: Aspirin, O-acetylsalicylic acid, acidum salicylicum, polopiryna.
  • History: Bark tea from white willow trees contained salicylic acid, prescribed by Hippocrates for fever and pain. However, oral salicylic acid caused severe gastrointestinal irritation due to high acidity. In 1897, Felix Hoffmann at Bayer synthesized acetylsalicylic acid by acetylating the phenolic group of salicylic acid, reducing gastric irritation. Bayer began commercial marketing in 1899. ASA belongs to the Non-Steroidal Anti-Inflammatory Drug (NSAID) class, lacking a steroidal cyclopentanoperhydrophenanthrene core.
• Synthesis (Esterification):   $\text{Salicylic Acid } (C_7H_6O_3) + \text{Acetic Anhydride } (C_4H_6O_3) \xrightarrow{H_2SO_4} \text{ASA } (C_9H_8O_4) + \text{Acetic Acid } (C_2H_4O_2)$

• Stoichiometric Calculation:
  • Reactants: $2\,g$ Salicylic Acid ($SA$, MW = 138) + $4\,mL$ Acetic Anhydride ($AA$, MW = 102, $d = 1.08\,g/mL$).
  • Yield calculations:
  • From Salicylic Acid:       $2\,g\,SA \times \frac{1\,mol\,SA}{138\,g} \times \frac{1\,mol\,ASA}{1\,mol\,SA} \times \frac{180\,g}{1\,mol\,ASA} = 2.61\,g\,ASA$
  • From Acetic Anhydride:       $4\,mL \times 1.08\,g/mL = 4.32\,g\,AA$$4.32\,g\,AA \times \frac{1\,mol\,AA}{102\,g} \times \frac{1\,mol\,ASA}{1\,mol\,AA} \times \frac{180\,g}{1\,mol\,ASA} = 7.62\,g\,ASA$
  • Limiting reactant = Salicylic Acid. Theoretical yield = $2.61\,g$ ASA. If actual yield = $1.00\,g$, the percentage yield is:     $\text{Percentage Yield} = \frac{1.00\,g}{2.61\,g} \times 100 = 38.31\text{\%}$
• Physical and Chemical Identification:
  • Physical properties: Colorless/white crystalline powder, odorless, MP = $135\,^\circ\text{C}$.
  • Acid Hydrolysis Test: ASA heated with water and $HCl$ hydrolyzes to salicylic acid. Adding $FeCl_3$ produces a deep violet color due to the phenolic group of salicylic acid.
  • Basic Hydrolysis Test: Forms a clear solution of sodium acetylsalicylate, which crystallizes upon cooling.
• Clinical Indications and Dosing:
  • Analgesic & Antipyretic: $325\text{-}650\,mg$ adult dose.
  • Anti-inflammatory: $45\,mg/kg$ daily adult dose.
  • Antiplatelet / Antithrombotic: Low dose of $40\text{-}80\,mg$ daily (commonly $81\,mg$ enteric-coated tablets).
• Pharmacodynamics:
  • Non-selective irreversible inhibitor of Cyclooxygenase (COX-1 and COX-2) enzymes.
  • Inhibition of COX-1 reduces protective gastric prostaglandin synthesis, predisposing to NSAID-induced gastric ulcers. Selective COX-2 inhibitors (e.g., celecoxib, rofecoxib) spare COX-1, though celecoxib carries cardiovascular black-box warnings.
  • Irreversible acetylation of COX-1 in platelets inhibits Thromboxane $A_2$ ($TXA_2$) synthesis, preventing platelet aggregation for the lifetime of the platelet ($7\text{-}10$ days).
  • ASA does not inhibit the Lipoxygenase (LOX) pathway. Shunting arachidonic acid into the LOX pathway increases leukotrienes, inducing severe bronchospasm in asthmatic patients.

• Contraindications:
  • Active peptic ulcer disease, bleeding/hemostatic disorders, severe asthma (aspirin-induced triad), gout (ASA competes with uric acid renal excretion), G6PD deficiency, Dengue fever, and viral infections in children/adolescents (risk of Reye's syndrome).
• Salicylate Plasma Toxicity Scale:
  • $< 10\,mg/dL$: Analgesic, antipyretic, antiplatelet effects.
  • 10\text{-}50\,mg/dL$: Anti-inflammatory and uricosuric effects. Tinnitus develops near 50\,mg/dL$.
  • 50\text{-}80\,mg/dL$: Mild intoxication characterized by central hyperventilation.\n - 80\text{-}110\,mg/dL$: Moderate intoxication; fever, severe dehydration, metabolic acidosis.
  • $110\text{-}160\,mg/dL$: Severe toxicity; vasomotor collapse, coma, hypoprothrombinemia.\n - > 160\,mg/dL$: Lethal concentration causing acute renal and respiratory failure.\n\n\n\n- Toxicology Management:\n - Gastric decontamination with activated charcoal (adsorbent).\n - Intravenous Sodium Bicarbonate to alkalinize urine. Alkalinizing urine converts nonpolar salicylic acid into ionized salicylate (HIPE$: Hydrophilic, Ionized, Polar$\rightarrow Excreted), preventing renal reabsorption.\n - Hemodialysis in life-threatening toxicity.\n- Representative Ester Structures:\n - Isopentyl acetate (banana scent): Derived from acetic acid and isopentyl alcohol.\n\n\n\n - Octyl formate (orange scent): Derived from formic acid and octanol.\n\n\n\n\n# Synthesis, Purification, and Metabolism of Acetanilide\n\n- Acetanilide properties:\n - Chemical formula: C_8H_9NO$or$C_6H_5NH(COCH_3)$(Molar mass =$135\,g\,mol^{-1}).\n - IUPAC name: N-phenylacetamide. Synonyms: Acetanil, 2-acetanilide, acetacetylamine, antifebrin.\n - An amide derivative formed from the condensation of an acid part (acetyl group) and an amino part (aniline).\n\n\n\n - Physical properties: White odorless leaflets or shiny flakes, MP = 114\text{-}116\,^\circ\text{C}$, BP =$304\,^\circ\text{C}$, specific gravity =$1.219. Soluble in hot water; sparingly soluble in cold water.\n\n\n\n- Experimental Preparation (Acetylation):\n - Due to volatile and irritating acetic anhydride vapor, reactions must be conducted in a chemical fume hood with the sash lowered.\n\n\n\n - Reagents: 1\,mL$Aniline ($d = 1.02\,g/mL$, MW = 93) +$2\,mL$Acetic Anhydride ($d = 1.08\,g/mL, MW = 102).\n - Acetylation reagents comparison:\n - Acetyl chloride + Aniline \rightarrow$Acetanilide +$HCl\n\n\n\n - Acetic anhydride + Aniline \rightarrow$Acetanilide + Acetic Acid ($CH_3COOH)\n\n\n\n\n\n\n\n- Purification:\n - The crude product is purified by recrystallization from hot water. The solution is heated in a water bath until dissolved, cooled to room temperature, and placed in an ice bath to precipitate pure white crystals. Crystals are washed with ice-cold HCl and water, then dried.\n\n\n\n- Stoichiometric Calculation:\n - Reactant masses:\n - Aniline (An$):$1\,mL \times 1.02\,g/mL = 1.02\,g\,An\n      1.02\,g\,An \times \frac{1\,mol\,An}{93\,g} \times \frac{1\,mol\,Ac}{1\,mol\,An} \times \frac{135\,g}{1\,mol\,Ac} = 1.48\,g\,\text{Acetanilide}\n - Acetic Anhydride (AA$):$2\,mL \times 1.08\,g/mL = 2.16\,g\,AA\n      2.16\,g\,AA \times \frac{1\,mol\,AA}{102\,g} \times \frac{1\,mol\,Ac}{1\,mol\,AA} \times \frac{135\,g}{1\,mol\,Ac} = 2.85\,g\,\text{Acetanilide}\n - Aniline is the limiting reactant. Theoretical yield = 1.48\,g.\n - Percentage yield calculation if actual yield is 950\,mg$($0.95\,g):\n    \text{Percentage Yield} = \frac{0.95\,g}{1.48\,g} \times 100 = 64.19\text{\%}\n- Chemical Tests:\n 1. Acid Hydrolysis: Cleaves acetanilide into aniline and acetic acid. Nitration forms para-nitroaniline crystals.\n 2. Bromination: Electrophilic aromatic substitution of acetanilide yields 4-bromoacetanilide (mono-brominated product at the para position due to steric directing effects). In contrast, unsubstituted aniline yields 2,4,6-tribromoaniline.\n\n\n\n- Metabolism and Toxicology:\n - In vivo, acetanilide undergoes aromatic hydroxylation to produce acetaminophen (paracetamol), its active antipyretic/analgesic metabolite.\n - However, amide hydrolysis of acetanilide generates free aniline. Aniline undergoes N-hydroxylation to form phenylhydroxylamine, a toxic metabolite that oxidizes ferrous iron (Fe^{2+}$) in hemoglobin to ferric iron ($Fe^{3+}), producing methemoglobinemia and severe jaundice.\n\n\n\n- Structural Comparison of Analgesics:\n - Acetaminophen: Contains phenol and amide groups.\n\n\n\n - Aspirin: Contains carboxylic acid and ester groups.\n - Ibuprofen: Contains carboxylic acid and alkylated benzene ring.\n - Naproxen: Contains carboxylic acid, ether, and a naphthalene ring core.\n\n\n\n - Ketoprofen: Contains carboxylic acid, ketone, and aromatic benzene rings.\n\n\n\n\n# Synthesis, Properties, and Identification of Acetone\n\n- Acetone properties:\n - Chemical formula: CH_3COCH_3$(Molar mass =$58\,g\,mol^{-1}).\n - IUPAC name: Propan-2-one. Synonyms: Dimethyl ketone, 2-propanone, beta-ketopropan.\n - Structure: Simplest aliphatic ketone containing a central carbonyl group bonded to two methyl groups (R\text{-}CO\text{-}R').\n - Physical properties: Colorless, highly volatile, flammable liquid; BP = 56.2\,^\circ\text{C}$($133\,^\circ\text{F}).\n - Physiological relevance: Found in trace amounts in normal blood and urine. High blood concentrations (ketonemia) and urinary excretion (ketonuria) occur during starvation, low-carbohydrate diets, or uncontrolled Diabetes Mellitus. In uncontrolled diabetes, elevated ketone bodies cause ketoacidosis and characteristic "acetone breath".\n - Three main physiological ketone bodies:\n 1. Beta-hydroxybutyric acid (\sim 80\text{\%})\n 2. Acetoacetic acid (\sim 20\text{\%})\n 3. Acetone (trace amounts)\n- Industrial Uses:\n - Solvent for artificial fibers, explosives, paints, inks, adhesives, and nail-polish removers.\n - Alcohol denaturant; skin defatting agent before chemical peels.\n- Synthetic Methods:\n 1. Cumene Process (Hock Process): Reaction of benzene, propene, and oxygen yields acetone and phenol.\n\n\n\n 2. Wacker-Hoechst Process: Propylene undergoes Markovnikov hydration to form 2-propanol, which is oxidized to acetone.\n\n\n\n\n\n 3. Dry Distillation (Pyrolysis) of Acetates:\n     Ca(CH_3COO)_2 + 2Na(CH_3COO) \xrightarrow{\Delta} CH_3COCH_3 + Na_2CO_3 + CaCO_3\n\n\n\n 4. Acetone-Butanol-Ethanol Fermentation: Fermentation of carbohydrates using Clostridium acetobutylicum (obsolete industrially due to low yields).\n- Pyrolysis Stoichiometry Calculation:\n - Reactants: 7\,g$Calcium Acetate ($Ca(CH_3COO)_2$, MW = 158) +$7\,g$Sodium Acetate ($Na(CH_3COO), MW = 82).\n - Calculations:\n - From Calcium Acetate:\n      7\,g\,Ca(CH_3COO)_2 \times \frac{1\,mol}{158\,g} \times \frac{1\,mol\,\text{Acetone}}{1\,mol\,Ca(CH_3COO)_2} \times \frac{58\,g}{1\,mol\,\text{Acetone}} = 2.57\,g\n - From Sodium Acetate:\n      7\,g\,Na(CH_3COO) \times \frac{1\,mol}{82\,g} \times \frac{1\,mol\,\text{Acetone}}{2\,mol\,Na(CH_3COO)} \times \frac{58\,g}{1\,mol\,\text{Acetone}} = 2.475\,g\n - Calcium acetate is the limiting reagent for producing acetone in this yield pathway. Theoretical yield = 2.57\,g.\n - Percentage yield if actual yield is 1.00\,g:\n    \text{Percentage Yield} = \frac{1.00\,g}{2.57\,g} \times 100 = 38.91\text{\%}\n\n\n\n\n\n- Diagnostic Chemical Tests for Acetone:\n - Tollen's Test: Negative (solution remains clear and colorless because acetone resists oxidation).\n\n\n\n - Schiff's Test: Schiff's reagent (bulky nucleophile) cannot react with sterically hindered ketones. Aldehydes produce a brilliant purplish-pink (magenta) solution, whereas acetone yields a negative light pink/red-violet result.\n\n\n\n\n\n\n\n - Iodoform Test: Reaction of methyl ketones with iodine (I_2$) in$NaOH$or$NaOCl/KI$yields a brown solution and a yellow precipitate of iodoform ($CHI_3).\n\n\n\n - Bisulfite Addition: Addition of sodium bisulfite produces a crystalline white precipitate.\n- Clinical Ketonuria Diagnostics:\n - Acetone Test: Shaking urine with sodium nitroprusside and layering with ammonia produces a magenta ring at the interface.\n - Cyanide Nitroprusside Test (Brand's Test): Addition of sodium cyanide followed by sodium nitroprusside turns urine containing acetoacetate or acetone red/purple.\n- Representative Ketone Drugs: Methadone (potent opioid analgesic), Naloxone (opioid antagonist), Acetophenone, Oxycodone, Ketoprofen, Ketorolac.\n\n\n\n\n\n\n\n\n\n\n# Synthesis, Anesthetic Properties, and Toxicity of Chloroform\n\n- Chloroform properties:\n - Chemical formula: CHCl_3$(Molar mass =$119.5\,g\,mol^{-1}).\n - IUPAC name: Trichloromethane. Synonyms: Formyl trichloride, methane trichloride, methyl trichloride, TCM, Freon 20, R-20, UN 1888.\n\n\n\n- History:\n - Prepared in 1831 by Dr. Samuel Guthrie by mixing whiskey with chlorinated lime (calcium hypochlorite).\n - Anesthetic properties discovered in 1847 by Sir James Young Simpson.\n - First dental clinical application performed by Francis Brodie Imlach.\n\n\n\n- Physical Properties:\n - Colorless, volatile, sweetly-scented halogenated liquid with a burning sweet taste (40\times sweeter than sucrose).\n - Density = 1.49\,g/mL (denser than water); viscosity similar to water.\n - Immiscible in water (lacks hydrogen bonding capability); freely miscible with organic solvents.\n - Excellent solvent for fats, oils, gums, resins, iodine, and alkaloid extractions (e.g., morphine from opium poppies, scopolamine from Datura plants).\n- Anesthetic Mechanism and Toxicity:\n - Inhalational anesthesia MOA: Inhibits TRPC5 (Transient Receptor Potential) channels in the brain and acts as a positive allosteric modulator at GABA_A receptors.\n - Toxicity & Metabolites: Oxidized to Phosgene (COCl_2), carbene, and chlorine gas. Phosgene is hepatotoxic and nephrotoxic, causing centrilobular liver necrosis and renal failure. Classified as a Group 2B probable human carcinogen.\n - Acute Inhalation Effects:\n - < 1,500\,ppm: Dizziness, headache, fatigue.\n - 1,500\text{-}30,000\,ppm$: Surgical anesthesia.
  • 40,000\,ppm$: Fatal due to respiratory paralysis and cardiac arrhythmia.\n - Lethal oral dose: 10\,mL$($45\,g).\n- Synthesis Methods:\n 1. Methane Chlorination:\n     CH_4 + Cl_2 \rightarrow CH_3Cl + HCl\n     CH_3Cl + Cl_2 \rightarrow CH_2Cl_2 + HCl\n     CH_2Cl_2 + Cl_2 \rightarrow CHCl_3 + HCl\n     CHCl_3 + Cl_2 \rightarrow CCl_4 + HCl\n 2. Reduction of Carbon Tetrachloride: CCl_4 + 2H \xrightarrow{Fe/H_2O} CHCl_3 + HCl$.
  1. Haloform Reaction of Ethanol: Ethanol + Hypochlorous Acid ($HOCl$) $\rightarrow$ Chloroform.
  2. Haloform Reaction of Acetone with Calcium Hypochlorite:      $2CH_3COCH_3 + 6Ca(OCl)_2 \rightarrow 2CHCl_3 + Ca(CH_3COO)_2 + 2Ca(OH)_2 + 3CaCl_2$
• Laboratory Synthesis Calculation:
  • Reactants: $12\,g$ Acetone ($CH_3COCH_3$, MW = 58) + $150\,g$ Calcium Hypochlorite ($Ca(OCl)_2$, MW = 143).
  • Stoichiometric conversions:
  • From Acetone:       $12\,g\,\text{Acetone} \times \frac{1\,mol}{58\,g} \times \frac{2\,mol\,CHCl_3}{2\,mol\,\text{Acetone}} \times \frac{119.5\,g}{1\,mol\,CHCl_3} = 24.72\,g$
  • From Calcium Hypochlorite:       $150\,g\,Ca(OCl)_2 \times \frac{1\,mol}{143\,g} \times \frac{2\,mol\,CHCl_3}{6\,mol\,Ca(OCl)_2} \times \frac{119.5\,g}{1\,mol\,CHCl_3} = 41.78\,g$
  • Acetone is the limiting reactant. Theoretical yield = $24.72\,g$.
  • Percentage yield calculation if actual yield is $1.00\,mL$ ($1.49\,g$):     $\text{Percentage Yield} = \frac{1.49\,g}{24.72\,g} \times 100 = 6.03\text{\%}$
• Photo-oxidation and Storage Precautions:
  • Exposure to air and UV light oxidizes chloroform into toxic phosgene gas ($COCl_2$), which possesses a fresh-cut hay/grass odor:     $2CHCl_3 + O_2 \xrightarrow{\text{light}} 2COCl_2 + 2HCl$
  • To prevent oxidation, chloroform must be stored in amber or dark blue glass bottles filled to the brim, or stabilized by adding $1\text{\%}$ ethanol (which scavenges phosgene to form harmless diethyl carbonate).
  • Chemical tests: Non-flammable; pure chloroform produces no precipitate with alcoholic silver nitrate.
  • Spills: Liquid phosgene spills are neutralized with sodium bicarbonate; gaseous leaks are neutralized with ammonia vapor.

Preparation and Clinical Derivatives of Benzamide

• Benzamide properties:
  • Chemical formula: $C_6H_5CONH_2$ (Molar mass = $121\,g\,mol^{-1}$).
  • IUPAC name: Benzenecarboximidic acid. Synonyms: Benzoic acid amide, phenylcarboxamide, benzoylamide, benzoylamine.

• Physical properties: White powder, BP = $288\,^\circ\text{C}$. Slightly soluble in water, ethanol, and carbon tetrachloride.
  • Laboratory Synthesis:
• Reaction: Benzoyl chloride + Concentrated Ammonia $\rightarrow$ Benzamide + Hydrochloric acid.     $C_6H_5COCl + NH_3 \rightarrow C_6H_5CONH_2 + HCl$

• Procedure: In a fume hood, $5\,mL$ concentrated ammonia ($d = 0.73\,g/mL$, MW = 17) is treated dropwise with $1\,mL$ benzoyl chloride ($d = 1.21\,g/mL$, MW = 140.5). Precipitation occurs quickly; the mixture stands for $10\text{-}15$ minutes, is filtered by gravity, washed with ice-cold water, and dried.

• Stoichiometric Calculation:
  • Reactant masses:
  • Benzoyl Chloride: $1\,mL \times 1.21\,g/mL = 1.21\,g$$1.21\,g \times \frac{1\,mol}{140.5\,g} \times \frac{1\,mol\,\text{Benzamide}}{1\,mol} \times \frac{121\,g}{1\,mol\,\text{Benzamide}} = 1.042\,g$
  • Ammonia: $5\,mL \times 0.73\,g/mL = 3.65\,g$$3.65\,g \times \frac{1\,mol}{17\,g} \times \frac{1\,mol\,\text{Benzamide}}{1\,mol} \times \frac{121\,g}{1\,mol\,\text{Benzamide}} = 25.98\,g$
  • Benzoyl chloride is the limiting reactant. Theoretical yield = $1.04\,g$.
  • Percentage yield if actual yield is $1.00\,g$:     $\text{Percentage Yield} = \frac{1.00\,g}{1.042\,g} \times 100 = 95.97\text{\%}$ (or $96.15\text{\%}$).
• Substituted Benzamide Pharmaceutical Derivatives:
  • Sulpiride (Dogmatil): First-generation atypical antipsychotic.

• Amisulpride: Clinically established atypical antipsychotic.

• Metoclopramide (Plasil): Gastroprokinetic and antiemetic agent derived from para-aminobenzoic acid (PABA). Accelerates gastric emptying into the small intestine.
• Cisapride (Propulsid): Gastroprokinetic used for GERD and severe nocturnal heartburn.

• Procainamide (Pronestyl): Class 1A antiarrhythmic agent.

• Procarbazine (Hodpro): Antineoplastic agent for Stage III and IV Hodgkin's lymphoma.
• Moclobemide (Aurorix): Reversible Monoamine Oxidase A (MAO-A) inhibitor for major depressive disorder.

• Chemical Identification Tests:
  • Alkaline Hydrolysis: Heating benzamide with $NaOH$ liberates ammonia gas, turning red litmus paper blue.
  • Acid Hydrolysis: Heating with acid liberates benzoic acid, turning blue litmus paper red.
  • Reaction with Nitrous Acid: Generates nitrogen gas, visible as yellow effervescence along the test tube walls.

Preparation, Pharmacokinetics, Toxicity, and Chromatography of Acetaminophen

• Acetaminophen (Paracetamol / APAP) properties:
  • Chemical formula: $C_8H_9NO_2$ (Molar mass = $151\,g\,mol^{-1}$).
  • IUPAC name: N-(4-hydroxyphenyl)ethanamide or N-(4-hydroxyphenyl)acetamide.

• Aniline analgesic class. Widely used over-the-counter analgesic and antipyretic. Lacks meaningful peripheral anti-inflammatory activity and does not cause gastric ulceration.
• Pregnancy Safety Categories: Category B for oral/rectal administration; Category C for intravenous administration.
• Commercial Formulations: Biogesic ($500\,mg$, Philippines), Tylenol ($325\,mg$ regular, $500\,mg$ extra strength, US), Panadol ($500\,mg$, Europe).

• Laboratory Synthesis (Acetylation of 4-Aminophenol):
  • Reaction: 4-aminophenol ($C_6H_7NO$, MW = 109) + Acetic Anhydride ($C_4H_6O_3$, MW = 102) $\rightarrow$ Paracetamol + Acetic Acid.

• Reaction Mechanism:
  1. Nucleophilic attack: The lone pair on the primary amine nitrogen of 4-aminophenol attacks the electrophilic carbonyl carbon of acetic anhydride, forming a tetrahedral intermediate.

2. Proton transfer & intermediate collapse: Re-formation of the carbonyl double bond eliminates acetate, producing paracetamol and acetic acid.

• Experimental Steps:

- Suspend $1.5\,g$ 4-aminophenol in $7.4\,mL$ water, add $2\,mL$ acetic anhydride ($d = 1.08\,g/mL$), stir and heat at $120\,^\circ\text{C}$ on a hot plate.

- Precipitate forms within $2\text{-}5$ minutes. Cool in an ice bath to maximize crystallization.

- Collect crude brown product by suction filtration using a Buchner funnel.

- Purify crude product via hot filtration and recrystallization from water or $50:50$ methanol:water ($MeOH:H_2O$) with activated charcoal.

- Scratching inner glass walls with a glass rod induces crystal nucleation.

- Filter pure needle-like crystals on a Hirsch funnel and dry under vacuum with phosphorus pentoxide ($P_2O_5$).

- Melting point determination: Pure paracetamol melts at $169\text{-}171\,^a\text{C}$ (Theoretical: $169\text{-}170.5\,^a\text{C}$).

• Stoichiometric Calculation:
  • Reactant masses:
  • 4-aminophenol ($P$): $1.5\,g\,P \times \frac{1\,mol}{109\,g} \times \frac{1\,mol\,A}{1\,mol\,P} \times \frac{151\,g}{1\,mol\,A} = 2.08\,g\,\text{Paracetamol}$
  • Acetic Anhydride ($AA$): $2\,mL \times 1.08\,g/mL = 2.16\,g$$2.16\,g \times \frac{1\,mol}{102\,g} \times \frac{1\,mol\,A}{1\,mol\,AA} \times \frac{151\,g}{1\,mol\,A} = 3.20\,g\,\text{Paracetamol}$
  • Limiting reactant = 4-aminophenol. Theoretical yield = $2.08\,g$.
  • Percentage yield calculation if actual yield is $1.20\,g$:     $\text{Percentage Yield} = \frac{1.20\,g}{2.08\,g} \times 100 = 57.69\text{\%}$
• Multi-Step Synthesis from Aspirin to Paracetamol:
  • Pathway: Aspirin ($95\text{\%}$) $\xrightarrow{\text{acid hydrolysis}} (86\text{\%}) Salicylic Acid $\xrightarrow{\text{decarboxylation}} (51\text{\%}) Phenol $\xrightarrow{\text{nitration with dil } H_2SO_4/NaNO_3} (6\text{\%}) p-Nitrophenol $\xrightarrow{\text{reduction } NaBH_4/LiAlH_4} (58\text{\%}) p-Aminophenol $\xrightarrow{\text{acetylation}} (18\text{\%}) Paracetamol.\n - Overall Process Efficiency:\n    0.95 \times 0.86 \times 0.51 \times 0.06 \times 0.58 \times 0.18 = 0.0026 = 0.26\text{\%}\n\n\n\n\n\n\n\n\n\n\n\n- Commercial Combination Formulations:\n - Saridon: Paracetamol + Propyphenazone + Caffeine.\n - Alaxan: Paracetamol + Ibuprofen.\n - Buscopan Plus / Venus: Paracetamol (500\,mg$) + Hyoscine N-butylbromide ($10\,mg).\n - Neozep: Paracetamol + Phenylephrine + Chlorphenamine.\n - Relaks: Paracetamol (450\,mg$) + Orphenadrine ($35\,mg).\n - Solpadeine Plus / Panadeine: Paracetamol + Codeine + Caffeine.\n- Metabolism and Hepatotoxicity:\n - Hepatic Metabolic Fractions:\n - Glucuronidation (Major pathway, 55\text{\%}): Yields non-toxic paracetamol glucuronide.\n - Sulfation (Major pathway, 30\text{\%}): Yields non-toxic paracetamol sulfate.\n - Glutathione Conjugation (Minor pathway, 15\text{\%}): CYP450 monooxygenase hydroxylation converts paracetamol to N-acetyl-p-benzoquinone imine (NAPQI).\n\n\n\n\n\n - Toxicity Mechanism: Maximum recommended daily dose = 4\,g$($8 \times 500\,mg$tablets). Doses exceeding$20 tablets are fatal. Toxic overdoses saturate glucuronidation and sulfation, routing paracetamol into CYP450 oxidation to form excess NAPQI. NAPQI depletes hepatic glutathione and binds covalently to proteins in hepatocytes, causing acute centrilobular hepatic necrosis and renal tubular necrosis.\n - Antidote Treatment: N-acetylcysteine (NAC) administered orally (140\,mg/kg loading dose) restores hepatic glutathione stores to detoxify NAPQI.\n- Thin Layer Chromatography (TLC):\n - Evaluates purity, analyzes composition, and monitors reaction progress.\n - Components:\n - Stationary phase: Polar adsorbent (silica gel coated on glass or plastic plate).\n - Mobile phase: Organic solvent climbing the plate via capillary action.\n - Procedure: Spot sample using a glass capillary tube, develop in a closed TLC chamber, mark the solvent front, and visualize spots under short-wave UV light (254\,nm, showing dark quenching spots on fluorescent green silica) or iodine vapor (yellow spots).\n\n\n\n - Elution and Polarity Scale:\n - Least polar (fastest elution with nonpolar mobile phase): Alkanes \rightarrow$Petroleum ether$\rightarrow$Cyclohexane$\rightarrow$Carbon tetrachloride$\rightarrow$Toluene$\rightarrow$Chloroform$\rightarrow$Dichloromethane$\rightarrow$Diethyl ether$\rightarrow$Ethyl acetate$\rightarrow$Acetone$\rightarrow$2-Propanol$\rightarrow$Pyridine$\rightarrow$Ethanol$\rightarrow$Methanol$\rightarrow$Water$\rightarrow Acetic acid (Most polar).\n\n\n\n - Retention Factor (R_f) Calculation:\n    R_f = \frac{\text{Distance moved by spot center}}{\text{Distance moved by solvent front}}\n - Sample calculation: If a spot travels 28.0\,mm$and the solvent front travels$80.0\,mm:\n      R_f = \frac{28.0\,mm}{80.0\,mm} = 0.35$$