Planning conversions step by step

Work backwards

Suppose the task is: turn propan-2-ol into propan-1-ol. The target is primary, and the start is secondary. Ask which reaction makes a primary alcohol. One way is hydroboration of propene. Which reaction makes propene? Dehydration of propan-2-ol. The route is now clear: two steps. This habit, of starting at the target and asking what could make it, is the key skill.

The map

Most of the reactions of this chapter fit into one map.

• Alcohol to alkene: concentrated $\text{H}_2\text{SO}_4$, heat. Alkene to alcohol: water with acid (Markovnikov) or borane then alkaline peroxide (anti-Markovnikov).
• Alcohol to haloalkane: HX, $\text{PBr}_3$ or $\text{SOCl}_2$. Haloalkane to alcohol: aqueous KOH. Haloalkane to alkene: alcoholic KOH.
• Alcohol to carbonyl compound: oxidation. Carbonyl compound to alcohol: reduction.
• To make the carbon chain longer: a Grignard reagent with methanal (one carbon), with ethylene oxide (two carbons), or with another carbonyl compound (the carbons of that compound).
• Phenols and ethers: the Williamson synthesis for ethers, and the ring reactions of phenol.

Examples of planning

Ethanol to butan-2-ol. The target has four carbons and is secondary. Ethanol has two carbons. A secondary alcohol comes from an aldehyde and a Grignard reagent. Split the carbon chain around the OH carbon: $\text{CH}_3\text{CHO}$ and $\text{C}_2\text{H}_5\text{MgBr}$. Both come from ethanol: one portion is oxidised with PCC to ethanal, another is turned into bromoethane with $\text{PBr}_3$, then into the Grignard reagent with magnesium in dry ether. The two are combined, and water is added.

Methanol to ethanol. One carbon must be added. Convert methanol to bromomethane and then to the Grignard reagent $\text{CH}_3\text{MgBr}$. Add methanal, which is made by oxidising a second portion of methanol. After water, the product is ethanol.

Chlorobenzene to anisole. Heat with aqueous sodium hydroxide at 623 K and 300 atm. Acid gives phenol. Sodium hydroxide gives the phenoxide, and iodomethane gives anisole. A haloarene is never the halide of a Williamson synthesis, which is why phenol comes first.

Traps along the way

A carbocation can move. In substitution with HX and in dehydration, a carbocation forms. If a neighbouring carbon can give a hydrogen or a methyl group and the new carbocation is more stable, the group moves. Two examples:

• 3-Methylbutan-2-ol with HBr: the secondary cation takes a hydride from the neighbouring carbon and becomes tertiary. The main product is 2-bromo-2-methylbutane.
• 3,3-Dimethylbutan-2-ol with HBr: a methyl group moves, and the main product is 2-bromo-2,3-dimethylbutane.

A primary alcohol with a quaternary neighbouring carbon, such as 2,2-dimethylpropan-1-ol, cannot lose water without a shift, because a primary cation would be far too unstable. A methyl group moves as the water leaves, and the product comes from a tertiary cation.

Hydroboration does not shift. Because no carbocation forms, hydroboration is the way to put OH on the less substituted carbon without rearrangement.

A Grignard reagent dies on an acidic hydrogen. An OH group, a COOH group or water in the same flask destroys it at once. The group must be protected or the order of the steps changed.

Each step costs yield. If the steps give 90, 85 and 80 percent, the overall yield is about 61 percent. The longer the route, the more starting material it eats.

Practise with new numbers

Try it in Python

The program stores the map as a list of arrows and searches for the shortest route between two kinds of compound.

Common mistakes

• Starting at the beginning and hoping. Work backwards from the target.
• Ignoring a carbocation shift. A branched alcohol with HX or acid can give a rearranged product.
• Using acid hydration to make a primary alcohol. It gives Markovnikov products.
• Adding a Grignard reagent to a compound with an OH group.
• Averaging the step yields. They multiply.

Remember these

• Work from the target backwards, and write the reagent at each arrow.
• A Grignard reagent adds carbons: methanal one, ethylene oxide two.
• A secondary carbocation next to a tertiary carbon, or a quaternary carbon, can shift.
• Overall yield is the product of the step yields.

Check yourself

Try each one on your own first. If you are stuck, open a hint. Then check with Show the answer.

1. Give a three-step route from propan-2-ol to propanoic acid.

2. How can bromoethane be changed into propan-1-ol?

3. Why does 2,2-dimethylpropan-1-ol give a rearranged product with HBr?

4. A route has four steps, each with an 85 percent yield. What is the overall yield?

References

• A-Level and IB Chemistry texts, the sections on synthetic routes and organic conversions.
• Clayden, Greeves and Warren, Organic Chemistry, the chapters on carbocations and on organometallic reagents (Grignard reagents).
• NCERT Chemistry Part II (Class 12), Chapter 7.