Organic synthesis routes and preparative techniques

Introduction: The Art and Logic of Organic Synthesis

Welcome to one of the most exciting areas of chemistry: organic synthesis! In industry and medicine, chemists rarely find the molecules they need simply lying around in nature. More often, life-saving pharmaceuticals, modern dyes, and advanced materials have to be built from scratch using simpler starting chemicals. Don't worry if multi-step synthesis feels daunting at first; think of it like planning a journey on a subway map or following a recipe. Once you learn the individual connections between functional groups and master the core laboratory techniques used to isolate and purify your products, you will be able to navigate complex synthesis questions with confidence.

Note on related chapters: Detailed reaction mechanisms (curly arrows) are explored in "Reaction mechanisms and curly arrows", analytical identification in "Mass spectrometry and infrared spectroscopy" and "NMR spectroscopy", chromatography in "Chromatography: TLC and gas–liquid chromatography", and environmental metrics in "Green chemistry and sustainability in industry".

Section 1: Designing Multi-Step Organic Synthetic Routes

1.1 Functional Group Interconversions (FGI)

When you are asked to design a synthetic route to prepare a target molecule, work backwards using retrosynthetic analysis. Look at the functional groups present in your target molecule and ask: "What single reaction can produce this group, and what starting material would I need?" Repeat this step until you reach the specified starting material.

Here is a summary of the fundamental functional group interconversions encountered across the course:

1. Alkenes to Alcohols: Electrophilic addition with steam in the presence of an acid catalyst, e.g., \(\text{H}_3\text{PO}_4\) or concentrated \(\text{H}_2\text{SO}_4\).
2. Alcohols to Haloalkanes: Nucleophilic substitution using sodium halides and concentrated sulfuric acid (or concentrated \(\text{HCl}\) for tertiary alcohols).
3. Haloalkanes to Alcohols: Nucleophilic substitution by heating under reflux with aqueous alkali, e.g., \(\text{NaOH}\text{(aq)}\) or \(\text{KOH}\text{(aq)}\).
4. Alcohols to Carbonyls and Carboxylic Acids:

- Primary alcohol heated and distilled with acidified potassium dichromate(VI), \(\text{K}_2\text{Cr}_2\text{O}_7 / \text{H}_2\text{SO}_4\), produces an aldehyde.
- Primary alcohol heated under reflux with excess \(\text{K}_2\text{Cr}_2\text{O}_7 / \text{H}_2\text{SO}_4\) oxidises fully to a carboxylic acid.
- Secondary alcohol heated under reflux with \(\text{K}_2\text{Cr}_2\text{O}_7 / \text{H}_2\text{SO}_4\) oxidises to a ketone.
- Tertiary alcohols resist oxidation under these conditions.

1.2 Carbon-Carbon Bond Formation

A crucial challenge in organic synthesis is lengthening the carbon skeleton. Introducing a nitrile group (\(-\text{C}\equiv\text{N}\)) adds one additional carbon atom to an existing chain:

- Haloalkane to Nitrile: Heat under reflux with ethanolic potassium cyanide, \(\text{KCN}\text{(ethanolic)}\). The cyanide ion (\(:\text{CN}^-\)) acts as a nucleophile, replacing the halogen atom by nucleophilic substitution.
- Once formed, nitriles can be converted into other valuable functional groups:

- Hydrolysis of a Nitrile to a Carboxylic Acid: Heating a nitrile under reflux with aqueous acid (e.g., dilute \(\text{HCl}\)) hydrolyses the \(-\text{C}\equiv\text{N}\) group to a carboxylic acid (\(-\text{COOH}\)):
\(\text{R-CN} + 2\text{H}_2\text{O} + \text{H}^+ \rightarrow \text{R-COOH} + \text{NH}_4^+\)

1.3 Specific Reagents Provided on the Salters Data Sheet

Make sure you can recognise and deploy the specific synthetic conversions listed on your Chemistry B Data Sheet:

- Carbonyl Reduction: Aldehydes and ketones are reduced to primary and secondary alcohols, respectively, using sodium tetrahydridoborate(III), \(\text{NaBH}_4\), in aqueous or alcoholic solution.
- Acyl Chloride Formation: Carboxylic acids react with thionyl chloride, \(\text{SOCl}_2\), to produce highly reactive acyl chlorides (\(-\text{COCl}\)), accompanied by \(\text{SO}_2\) and \(\text{HCl}\) gases:
\(\text{R-COOH} + \text{SOCl}_2 \rightarrow \text{R-COCl} + \text{SO}_2\text{(g)} + \text{HCl}\text{(g)}\)
- Reduction of Nitroarenes: Nitrobenzene derivatives (\(-\text{NO}_2\)) are reduced to primary aromatic amines (\(-\text{NH}_2\)) by heating with tin (\(\text{Sn}\)) and concentrated hydrochloric acid (\(\text{HCl}\)), followed by treatment with alkali.

Key Takeaway: Always count the carbons in your starting material and your target. If the chain is longer in the target, look for opportunities to introduce a nitrile group via nucleophilic substitution before carrying out subsequent transformations.

Section 2: Preparative Techniques for Liquid Organic Products

Many organic liquids are volatile and flammable. Synthesising and isolating them safely and cleanly requires a sequential set of practical techniques.

2.1 Heating Under Reflux

Organic reactions involving volatile reactants are often slow at room temperature and require heating. However, open heating would cause volatile reactants and products to boil away and escape, posing a fire risk and drastically reducing product yield.

- Apparatus: A round-bottom or pear-shaped flask fitted vertically with a Liebig condenser, clamped securely over a heat source.
- Heating Source: Because organic compounds are typically flammable, an electric heating mantle or water bath must be used rather than an open Bunsen burner flame.
- Anti-bumping granules: A few small boiling stones or granules are added to the reaction flask before heating. They provide nucleation sites that promote smooth, even boiling and prevent violent bubbling ("bumping").
- Condenser setup: Cold water must enter the condenser jacket at the bottom and exit from the top. This ensures that the water jacket fills completely without trapping air bubbles, providing maximum cooling efficiency.
- Open top: The top of the reflux condenser must never be stoppered. Sealing the apparatus would create a closed system, leading to dangerous pressure build-up and a possible explosion.

2.2 Distillation

Once the reaction is complete, the crude liquid mixture contains the desired product along with unreacted starting materials, solvents, and side products. Simple distillation separates liquids based on differences in their boiling points:

- The round-bottom flask contains the crude reaction mixture and anti-bumping granules, connected to a still head, a downward-sloping condenser, and a receiving vessel.
- Thermometer Placement: The bulb of the thermometer must sit exactly level with the side-arm opening leading into the condenser. This ensures it records the true temperature of the condensing vapour passing into the receiver.
- The fraction boiling within the target product's boiling range is collected.

2.3 Separation and Solvent Washing (Using a Separating Funnel)

Distilled or crude liquid products frequently contain water-soluble impurities or traces of acid. A separating funnel is used to partition the components between two immiscible liquid layers:

Step 1: Pouring the mixture: Pour the crude organic mixture and an aqueous washing solution into the separating funnel.
Step 2: Shaking and venting: Insert the stopper, invert the funnel, and shake gently. Periodically open the tap while inverted to release built-up pressure (especially important if using carbonates).
Step 3: Removing acid impurities: Washing with aqueous sodium hydrogencarbonate, \(\text{NaHCO}_3\text{(aq)}\), neutralises acidic impurities. This produces \(\text{CO}_2\) gas, which must be vented regularly:
\(\text{H}^+\text{(aq)} + \text{HCO}_3^-\text{(aq)} \rightarrow \text{H}_2\text{O}\text{(l)} + \text{CO}_2\text{(g)}\)
Step 4: Layer identification: Allow the layers to settle and separate completely. The denser liquid forms the lower layer. To confirm which layer is aqueous, add a few drops of water: the drops will fall into and merge with the aqueous layer.
Step 5: Draining: Remove the stopper, open the tap, and run the lower layer out into a beaker. Close the tap, and pour the upper organic layer out through the top neck to avoid recontamination.

2.4 Drying the Organic Liquid

Even after separation, the organic liquid remains saturated with microscopic water droplets, appearing cloudy. An anhydrous inorganic salt is used as a chemical drying agent:

- Common drying agents include anhydrous magnesium sulfate (\(\text{MgSO}_4\)), anhydrous sodium sulfate (\(\text{Na}_2\text{SO}_4\)), or anhydrous calcium chloride (\(\text{CaCl}_2\)).
- Procedure: Add small spatulas of the drying agent to the liquid in a conical flask, swirl, and let stand for 10–15 minutes.
- Endpoint: Initially, the salt clumps together as it hydrates. Continue adding drying agent until it swirls freely as a fine powder (like a snow globe) and the liquid becomes completely clear rather than cloudy.
- Removal: Remove the hydrated drying agent by decanting or gravity filtration using fluted filter paper.

2.5 Final Redistillation

The dried, clear organic liquid is subjected to a final, careful distillation. Only the distillate that boils within \(\pm 1\text{ }^\circ\text{C}\) to \(2\text{ }^\circ\text{C}\) of the literature boiling point of the target compound is collected into a clean, pre-weighed vessel.

Key Takeaway: The standard sequence for preparing an organic liquid is: Reflux \(\rightarrow\) Distillation \(\rightarrow\) Washing in separating funnel \(\rightarrow\) Drying with anhydrous salt \(\rightarrow\) Final redistillation.

Section 3: Preparative Techniques for Solid Organic Products

When an organic synthesis produces a solid product (such as aspirin or a nitro compound), the techniques shift to filtration, recrystallisation, and melting point analysis.

3.1 Filtration Under Reduced Pressure (Vacuum Filtration)

Traditional gravity filtration is too slow for collecting crystalline organic products. Instead, vacuum filtration using a Büchner funnel and Büchner flask (connected to a vacuum pump or water aspirator) is used:

- A piece of circular filter paper is placed flat inside the perforated plate of the Büchner funnel and moistened with a few drops of cold solvent to create a tight seal.
- The vacuum pump is turned on, and the crystalline slurry is poured into the funnel.
- The suction pulls the liquid filtrate through rapidly into the flask, leaving the damp solid cake on the filter paper.
- The crystals are rinsed with a small volume of ice-cold solvent to wash away soluble impurities from the crystal surfaces without dissolving the crystals themselves.

3.2 Purification by Recrystallisation

The crude solid contains both soluble and insoluble impurities. Recrystallisation purifies the solid based on differences in solubility at elevated versus cold temperatures.

Step-by-Step Recrystallisation Procedure:

1. Selection of Solvent: The ideal solvent dissolves the desired compound sparingly at cold temperatures, but readily at high temperatures. Impurities should either be insoluble at high temperatures or remain fully soluble when cold.
2. Dissolving: Dissolve the impure solid in the minimum volume of hot solvent. Using a minimum volume ensures the solution is completely saturated, maximising crystal formation upon cooling.
3. Hot Filtration (if necessary): If insoluble solid impurities are present, filter the hot solution rapidly through fluted filter paper in a pre-warmed glass funnel. The warmth prevents premature crystallisation of the product in the funnel stem.
4. Cooling: Allow the clear hot solution to cool slowly to room temperature, and then place it in an ice bath. Slow cooling encourages large, pure crystals to form, leaving soluble impurities dissolved in the cold solvent ("mother liquor").
5. Vacuum Filtration: Collect the pure crystals using a Büchner funnel under reduced pressure.
6. Washing and Drying: Wash the collected crystals with a minimal volume of ice-cold solvent. Dry the crystals between folds of filter paper or in a low-temperature desiccator/oven.

3.3 Assessing Purity: Melting Point Determination

Once dry, the purity of the solid is verified by measuring its melting point using a melting point apparatus or an oil bath:

- A small sample of powdered, completely dry solid is packed into a thin glass capillary tube sealed at one end.
- The tube is placed in the melting point apparatus and heated slowly (especially near the anticipated melting point, typically at \(1\text{ }^\circ\text{C}\) to \(2\text{ }^\circ\text{C}\) per minute).
- The temperature at which melting first begins and the temperature at which the last crystal disappears are recorded as the melting point range.

Interpreting Melting Point Data:

- Pure compound: Melts sharply over a very narrow range (usually within \(1\text{ }^\circ\text{C}\) to \(2\text{ }^\circ\text{C}\)) matching the published literature value.
- Impure compound: Impurities disrupt the regular crystalline lattice. As a result, an impure solid melts over a broad range and at a lower temperature (melting point depression) than the literature value.

Key Takeaway: Pure solids have sharp, distinct melting points. Recrystallisation exploits solubility temperature dependence, and using the minimum volume of hot solvent ensures maximum recovery.

Section 4: Quantitative Calculations in Preparative Chemistry

4.1 Percentage Yield

In practice, the amount of pure product obtained (actual yield) is almost always lower than the maximum theoretical amount calculated from the balanced equation (theoretical yield).

Reasons for reduced yield include: incomplete or equilibrium reactions, competing side reactions producing by-products, and mechanical losses during transfer, filtration, or recrystallisation.

The formula to recall is:

\(\text{Percentage yield} = \frac{\text{actual yield}}{\text{theoretical yield}} \times 100\)

Worked Example:
A student synthesises ethyl ethanoate by reacting \(6.00\text{ g}\) of ethanoic acid (\(M_r = 60.0\)) with an excess of ethanol:
\(\text{CH}_3\text{COOH} + \text{CH}_3\text{CH}_2\text{OH} \rightleftharpoons \text{CH}_3\text{COOCH}_2\text{CH}_3 + \text{H}_2\text{O}\)
After purification, the student isolates \(5.28\text{ g}\) of pure ethyl ethanoate (\(M_r = 88.0\)). Calculate the percentage yield.

1. Calculate moles of limiting reactant (\(\text{CH}_3\text{COOH}\)):
\(n(\text{CH}_3\text{COOH}) = \frac{m}{M} = \frac{6.00}{60.0} = 0.100\text{ mol}\)
2. Calculate theoretical moles and mass of product (\(1:1\) stoichiometric ratio):
\(n(\text{theoretical}) = 0.100\text{ mol}\)
\(m(\text{theoretical}) = n \times M = 0.100 \times 88.0 = 8.80\text{ g}\)
3. Calculate percentage yield:
\(\text{Percentage yield} = \frac{5.28\text{ g}}{8.80\text{ g}} \times 100 = 60.0\%\)

4.2 Atom Economy

While percentage yield tells you how efficiently a reaction has run in terms of mass recovery, atom economy measures how inherently "waste-free" the balanced chemical equation is.

The formula to recall is:

\(\text{Atom economy} = \frac{\text{mass of desired product}}{\text{total mass of products}} \times 100\)

Note: By conservation of mass, the total mass of products equals the total mass of reactants. Addition reactions have an atom economy of \(100\%\), whereas substitution and elimination reactions generate by-products and thus have lower atom economies.

4.3 Apparatus Uncertainties and Margins of Error

In all practical evaluations, experimental measurements carry an inherent uncertainty based on the precision of the measuring instrument:

\(\text{Percentage error} = \frac{\text{uncertainty}}{\text{measured value}} \times 100\)

- For instruments where two readings are taken to determine a single value (e.g., a balance taring or taking initial and final masses; a burette start and finish volume), the uncertainty must be multiplied by 2:
\(\text{Percentage error} = \frac{2 \times \text{instrument uncertainty}}{\text{measured quantity}} \times 100\)
- Minimising errors: Using larger masses or larger titre volumes reduces the overall percentage error in your experimental results.

Section 5: Laboratory Safety and Hazard Management

A Level examination questions routinely assess your ability to identify hazards and design safe practical setups. You must be able to specify precautions tailored to the chemical properties of the substances used:

- Flammable liquids (e.g., ethanol, propanone, cyclohexane): Keep well away from naked flames. Always heat using an electric mantle, water bath, or hot plate.
- Corrosive substances (e.g., concentrated \(\text{H}_2\text{SO}_4\), \(\text{SOCl}_2\), \(\text{NaOH}\)): Wear safety goggles and protective nitrile gloves. Keep eyewash stations accessible.
- Toxic or irritant vapours (e.g., \(\text{SO}_2\), \(\text{HCl}\text{(g)}\), \(\text{Br}_2\), volatile cyanides): Always handle in a functioning fume cupboard.

Summary: Common Exam Traps to Avoid

- Condenser water flow: Never show water entering at the top of a condenser. It enters at the bottom and leaves at the top.
- Sealed systems: Never place a stopper in the top of a reflux condenser or on a distillation receiver adapter. Pressure build-up will cause glassware to shatter.
- Thermometer position: Do not dip the thermometer into the boiling flask in a distillation setup. The bulb must sit right opposite the condenser side-arm.
- Recrystallisation solvent volume: Never add excess solvent. Always use the minimum volume of hot solvent to avoid dissolving the crystals permanently.
- Washing crystals: Never wash filtered crystals with warm or hot solvent; always use a small amount of ice-cold solvent.