Synthetic Cannabinoids and Signal Patterns

Synthetic cannabinoids (SC) are designer drugs that aim to mimic the pharmacological effect of the natural cannabinoid (−)-trans-Δ⁹-tetrahydrocannabinol (THC). Many SCs have an even higher binding affinity to the CB₁ receptor, which is responsible for the psychoactive effects, than THC.^[1] In the early 2000s, before SCs and other designer drugs were categorically illegalized by new NPS legislations, they were semi-legally sold as herbal incense mixtures, called "spice", consisting of dried plant material with sprayed on SCs.

There is a lot more to talk about SCs, but I'll keep that for future blog posts.

The compounds I picked for today's blog do vary only very slightly from each other in their molecular structure. For 5F-PB-22 only one hydrogen atom of the terminal CH₃ group in the alkyl chain is formally exchanged with a fluorine atom compared to PB-22. NM2201 does have a naphtyl substituent attached to the ester function instead of the 8-quinolinyl fragment in 5F-PB-22 and PB-22. Formally, one nitrogen atom is exchanged with a carbon atom. So, I think it is fair to say that these compounds are very similar in their molecular structure.

Now, importantly, as we have discussed before in another blog post and a recent publication similar compounds result in similar ¹H NMR spectra, which is the reason why benchtop NMR gives great possibilities for flagging new designer drugs. At first glance it might even not be easy to spot the differences in the spectra of these compounds, so let me guide you through this.

Figure 1. Stacked 60 MHz ¹H NMR spectra of three structurally closely related synthetic cannabinoids.

In Figure 1, I have stacked the 60 MHz ¹H NMR spectra of the SCs PB-22, 5F-PB-22, and NM2201. Let's look at the top and middle spectra first.

Again, the only difference of PB-22 and 5F-PB-22 is this one fluorine atom attached to the terminal carbon in the N-alkyl chain. The aromatic regions of the two spectra look almost exactly the same, except for a slight shift of singlet 3 to higher frequencies in 5F-PB-22.

Much more obvious are the differences in the spectra in the region 5 to 1 ppm. In 5F-PB-22, the CH₃ signal 8 is absent, and we observe apparently two new signals 9. I say 'apparently' because this actually is only one signal, namely a doublet of triplets (dt) and the reason why I wanted to write this post. The triplet part comes from the ³J_HH coupling with the neighboring CH₂ group. As ¹⁹F itself is NMR active, I = 1/2, it couples with ¹H. The geminal coupling of the fluorine atom with the two hydrogen atoms in the CH₂F group 9 is strong with ²J_HF = 47.5 Hz, which agrees well with what we would expect (a freely accessible overview of coupling constants can be found on the website of the NMR Facility of UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences).

If you have any questions about J couplings or illicit drug analysis via benchtop NMR, please don't hesitate to contact us.

[1] https://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoids_en (accessed May 19, 2022)