Synthesis planning and combined structural evidence

What you’ll learn

• Plan functional-group changes while tracking the carbon skeleton.
• Predict carbon-chain extension with organomagnesium reagents.
• Combine analytical evidence and calculate an overall yield.

Understand the idea

Start a synthesis plan by comparing the starting and target carbon skeletons, then identify which functional groups must change. Track every carbon through each proposed step: a nitrile carbon becomes part of the longer chain, and oxidation or reduction usually changes functionality without changing carbon count. A scheme can be worked backwards from the target to a familiar precursor and then checked forwards for compatibility.

At a conceptual level, an organomagnesium reagent contains a carbon with nucleophilic character. Its reaction with a carbonyl forms a new carbon–carbon bond; after protonation, methanal gives a primary alcohol, another aldehyde gives a secondary alcohol and a ketone gives a tertiary alcohol. Carbon dioxide instead provides one additional carbon and ultimately a carboxylic acid. Such reagents are destroyed by proton donors, so a proposed substrate containing an unprotected OH or COOH group is incompatible with that simple scheme.

Structural deductions should jointly satisfy elemental composition, accurate molecular mass, functional-group reactions, infrared bands and both carbon and proton NMR data. A plausible single spectrum is not enough if another observation conflicts. In a multi-step sequence, multiply fractional yields to calculate the overall yield; adding percentage yields is meaningless. Evaluate selectivity and purification as well as theoretical atom accounting when comparing routes.

Key formulae

$$\mathrm{RMgX+R'CHO\longrightarrow R'CH(OMgX)R\longrightarrow R'CH(OH)R}\quad\text{(protonation in final step)}$$

$$\mathrm{RMgX+CO_2\longrightarrow RCOOMgX\longrightarrow RCOOH}\quad\text{(protonation in final step)}$$

$$\text{overall fractional yield}=\prod_i\text{fractional yield}_i$$

$$\text{percentage yield}=100\frac{\text{actual amount}}{\text{theoretical amount}}$$

Worked example

Predict the alcohol skeleton formed by conceptual addition of an ethyl organomagnesium reagent to ethanal, followed by protonation.

1. Ethanal supplies its carbonyl carbon, one hydrogen and one methyl group at the future alcohol carbon.
2. The ethyl group adds to that carbon and creates a new carbon–carbon bond.
3. The product carbon bears OH, H, CH₃ and CH₂CH₃; the four-carbon chain has its OH group at carbon 2.

Answer: Butan-2-ol, a secondary alcohol; in an achiral environment the newly formed stereocentre gives a racemic product.