Past exam of the chemistry B course of the University of Cambridge / 2024 / Paper 1 / B1 / a

An enolate is an ambident nucleophile: the negative charge is concentrated toward oxygen, while its occupied conjugated orbital also has substantial reactive amplitude at the alpha carbon. An alkyl iodide presents an accessible, polarizable carbon electrophile. carbon attack through an SN2 reaction is generally kinetically favorable, while the more strongly charged oxygen is often coordinated to the counterion or solvated. The carbonyl reforms as the new C–C bond is made.carbon alkylation restores the carbonyl and makes the new C–C bond. oxygen alkylation instead gives an enol ether. The two outcomes are not resonance contributors of one product, and their ratio is not determined just by where the largest formal negative charge is drawn. electrophile, counterion, solvent and aggregation can change selectivity; hard silicon electrophiles and suitable acylating reagents often favor oxygen trapping. Product stability alone would not explain an irreversible kinetic choice.

Lithium diisopropylamide removes an alpha proton from the ethyl side of the ketone. The C–H electrons form the C=C part of a lithium enolate, while the C=O pi electrons move to oxygen. The phenyl side has no competing alpha C–H site. Diisopropylamine is the conjugate-acid byproduct.The carbon end of this enolate attacks the primary carbon bearing iodine in $\mathrm{IC}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{OMe}$. The C–I bond breaks to iodide in an SN2 reaction, and carbonyl reformation givesThus a three-carbon methoxypropyl chain is attached at the ketone alpha carbon. The remote methyl ether survives. The hindered amide base is chosen to generate the enolate rather than to add to the carbonyl. No absolute stereochemical preference is specified for the new stereocenter under these achiral conditions.

The initial nucleophile attacks silicon, not the nitrile or an alkene carbon. Each trimethylsilyl group has an electrophilic Si center. A methyl group from methyllithium attacks Si, passing through a pentacoordinate silicon arrangement; Si–O cleavage releases $\mathrm{SiM}{\mathrm{e}}_4$ and the lithium salt of the oxygen-containing fragment. Cleaving the silyl enol ether generates a lithium enolate; cleaving the aryl silyl ether generates a phenoxide. Neither operation needs a new deprotonation at a carbon stereocenter.Here $R-O^{-}$ represents either the phenoxide or the oxygen-centered enolate contributor. Excess reagent permits both cleavages. The pre-existing methyl/nitrile stereocenter retains its configuration: it has no hydrogen to remove, and neither bond attached to that center is broken.

After HMPA is added, each anionic oxygen attacks the carbonyl carbon of allyl chloroformate. The C=O pi electrons move to the carbonyl oxygen, giving a tetrahedral intermediate; collapse expels chloride. The enolate becomes an allyl enol carbonate, and the phenoxide becomes an aryl allyl carbonate, each containing $\mathrm{O}-\mathrm{C}(\mathrm{O})-\mathrm{OC}{\mathrm{H}}_2\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$. oxygen acylation accounts for preservation of the enol double bond and for the two newly installed carbonate groups. carbon attack would give a different carbon skeleton. The two oxygens are trapped because they were selectively unmasked by desilylation, rather than because every ether oxygen in the molecule is equally reactive.

HMPA coordinates Li${}^{+}$ through its phosphoryl oxygen and makes the anionic oxygen sites more available for acylation. Strong cation solvation changes contact ion pairing, chelation and aggregate structure. It can therefore accelerate trapping of both the enolate and phenoxide by the chloroformate, helping realize the observed O-acylation pathway.

It is too strong to assert that HMPA necessarily produces completely free, monomeric anions. In a primary study of a lithium enolate in THF, low-temperature multinuclear NMR and reaction kinetics identified an HMPA-coordinated dimer as the reactive form, even with excess HMPA.^[ref] The useful conclusion here is altered lithium coordination and enhanced oxygen accessibility; the exact aggregate of this bifunctional substrate is not supplied.