How are organic compounds with radioactive atoms synthesized? [closed]

Question

We often see reactions such as these in textbooks to highlight how reaction mechanisms work:

How are the radioactive substrates required for these mechanisms synthesized in the first place? There seems to be no easy way of just 'substituting' a radioactive atom in place of a non-radioactive one (especially for Benzene-14C, it might be easier to make a radioactive sodium salt using $\ce{^{24}Na}$). Also, Once the substrate is synthesized, how is it separated and purified? I'm assuming that the physical properties of these radioactive substrates would be very similar to their non-radioactive counterparts, which would make it very difficult to do so.

Answer 1

The current methods employed for synthesis fall into the following three categories¹:

• Chemical synthesis
• Biochemical methods
• Isotope exchange reactions

Chemical Synthesis:

Most chemical syntheses involving $\ce{^14 C}$ are done with Grignard reagent and $\ce{^14 CO2}$ or $\ce{^14 CN-}$. As an example, Benzene-14 is synthesized as such²:

Basic preparatory methods such as the above have been worked out long ago. An example of a more complex synthesis would be preparation of 18F-Fluorodeoxyglucose:

Biochemical methods

A few examples of these, as mentioned in (1), are:

High yields of [U-14C]sucrose, up to 70% based on $\ce{^14 CO2}$, are obtainable in detached leaves after a few hours photosynthesis using tobacco or Canna indica leaves for example.

DNA labelled either with $\ce{^14 C}$ or with $\ce{^3 H}$ is prepared by feeding E.coli with the correspondingly labelled thymine precursor. Similarly, by feeding [$\ce{^35 S}$]sulphate to E.coli or to yeast cells, isolation and hydrolysis of the proteins yields L.[$\ce{^35S}$]methionine and L-[$\ce{^35 S}$]cystine in radiochemical yields of 30% and 10% respectively.

Another example is the synthesis of C-14 labelled Phenylpyruvic acid³

Isotope exchange reactions

These are fairly common for atoms that can easily be exchanged, such as replacing $\ce{^23 Na}$ for $\ce{^24 Na}$, which was mentioned in the question. Another common mechanism for synthesis of Hydrogen isotope compounds is Hydrogen-Deuterium exchange. A similar mechanism also allows hydrogen-tritium exchange⁴.

Purification of radiolabelled compounds

This is mainly done through Chromatography¹, as the amount of radiolabelled substrate required is generally quite small. High-performance liquid chromatography is used to separate the compounds. The chemical identity of the compounds is confirmed by co-chromatographic behaviour with the unlabelled compound.

For further information, refer to the references (1) and (3), which go into a lot more detail with regards to the synthesis of these compounds.

References:

1. Anthony Evans, E. “Synthesis of Radiolabelled Compounds.” Journal of Radioanalytical Chemistry, vol. 64, no. 1–2, Mar. 1981, pp. 9–32. doi:10.1007/BF02518337.
2. Schmid, K., et al. “A Simple Method of Preparing Labeled Benzene.” Advances in Tracer Methodology, edited by Seymour Rothchild, Springer US, 1966, pp. 37–44. doi:10.1007/978-1-4684-8625-4_5.
3. Atzrodt, Jens, and John Allen. “Synthesis of Radiolabeled Compounds for Clinical Studies.” Drug Discovery and Evaluation: Methods in Clinical Pharmacology, edited by Hans Gerhard Vogel et al., Springer Berlin Heidelberg, 2011, pp. 105–18. doi:10.1007/978-3-540-89891-7_12.
4. Englander, S. W., and J. J. Englander. “[3] Hydrogen—Tritium Exchange.” Methods in Enzymology, vol. 49, Academic Press, 1978, pp. 24–39. doi:10.1016/S0076-6879(78)49005-6.