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Imagine that you want to make chlorobenzene with a carbon-14 label in one site only, the only site you want it to be in is on the carbon bearing the chlorine. Can you think of a better and shorter synthesis from a labelled C1 compound such as methyl iodide or barium carbonate ? The literature method is

BaCO3 --> CO2 --> Acetic acid --> Ethyl acetate

Next react with pent-1,5-diyl magnesium bromide to form 1-methylcyclohexan-1-ol

Dehydrate to 1-methylcyclhex-1-ene, dehydrogenate with palladium to toluene, convert to benzoic acid with an oxidant, use sodium azide and acid to make aniline. Last use nitrous acid and copper(i) chloride on the aniline to make the chlorobenzene. I count ten reactions.


My suggestion is to react labeled nitromethane with formaldehyde Then dehydrate to make nitroethene Use the nitroethene for a Diels-Alder reaction with furan Dehydrate with an acid to make labeled nitrobenzene Reduce with hydrogen and palladium on carbon to make aniline React thw aniline with nitrous acid to form the diazonium salt Convert the diazonium salt with copper(I) chloride to the target molecule.

This is seven steps, can anyone come up with a shorter synthesis ?

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  • $\begingroup$ Loosely related: How are organic compounds with radioactive atoms synthesized? $\endgroup$
    – Loong
    Feb 5, 2022 at 18:53
  • $\begingroup$ Reaction of dichlorocarbene with cyclopentadiene is reported to produce 6-chlorofulvene and\or chlorobenzene (58% yield) depending upon carbene precursor and reaction conditions. Note that the fulvene could likely be thermally rearranged to the chlorobenzene. The reaction producing chlorobenzene also seems site specific as the same reaction with indene is reported to produce only 2-chloronaphthalene (69% yield). $\endgroup$
    – ron
    Feb 5, 2022 at 21:14
  • $\begingroup$ (Cont.) Since $\ce{^{13}C}$ labeled chloroform is commercially available, this small-scale route could likely be optimized to produce the desired $\ce{^{13}C}$ labeled chlorobenzene in one or two steps depending how you count. $\endgroup$
    – ron
    Feb 5, 2022 at 21:15
  • $\begingroup$ Did you consult a database (like Reaxys [Elsevier], or Scifinder [The American Chemical Society]) for already known and published protocols? Because how else entered #587958 in the catalogue of Sigma-Aldrich ... (to mention one commercial supplier [though synthesis on demand]). $\endgroup$
    – Buttonwood
    Feb 5, 2022 at 22:38
  • $\begingroup$ I did consult Reaxys for the literature method, see J. Am. Chem. Soc. 1968, 90, 6, 1601–1605 Journal of the American Chemical Society, 1973, vol. 95, p. 8358,8363 Journal of labelled compounds and radiopharmaceuticals, 2004, vol. 47, # 4, p. 266 – 267 for the literature met hod $\endgroup$ Feb 6, 2022 at 5:27

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