"inherited procedural wisdom" may hold an organic chemist back in finding the true or correct answer. part v the synthesis of fentanyl and its analogues are illustrated in this skeletal diagram. part v the third case studied here is alpha-methylfentanyl. this group contains a substitution similar to the 3-methylfentanyl that was examined in the previous example on the previous image in this series (fentanyl synthesis p4.png), but it is on the phenethyl chain as opposed to being implanted on the piperidine ring. we then mark the two stereocenters, one on the c-4 carbon just as on fentanyl itself, and the other on the c-α (alpha carbon). to analogize these stereocenters we chose n-(1-hydroxyethyl)-4-hydroxypiperidine. when we draw out all potential stereoisomers, we see that the c-4 stereocenter is super-imposable, eliminating it as a true stereocenter. this leaves only 2 r/s assignments that follow the orientation of the stereocenter at the c-α (alpha carbon) position for the real α-methylfentanyl. these are labeled 7s and 7r, a reflection of the stereocenter in the piperidine derivative we used being at c-7 position. it is interesting that the c-4 stereocenter, which has no chiral activity in fentanyl (1st example), activiates it in 3-methylfentanyl with a on-the-ring addition, and loses it again in α-methylfentanyl with an off-the-ring addition. the fourth case studied here is ohmfentanyl. ohmfentanyl has 3 potential stereocenters, which are best analogized by another piperidine derivative: n-(1-hydroxyethyl)-3-methyl-4-hydroxypiperidine. this uses a similar structure to analogize the three potential stereocenters in ohmfentanyl, namely the 4-c, the 3-c, and the β-c (beta carbon). these three stereocenters are analogized in the c-4, c-3, and c-7 respectively. when we draw all potential stereoisomers out we see that they are not super-imposable in any combination of pairing, and therefore we have 8 unique stereoisomers and 3 true stereocenters. this yields 8 unique r/s assignment combinations which are outlined as captions under the stereoisomers of the analogous molecule. these fundamentals are typically enough to help a chemists navigate the world of fentanyl analogues proficiently. other substituents and substitutions generally follow the naming conventions outlined in this section. however, the presence of three six-membered rings which can each be independently substituted can easily lead to confusion, especially with the inconsistent use of prime notation. the structures of 4-methylfentanyl (left), 4'-methylfentanyl (centre) and 4"-methylfentanyl (right) the structures of 3-methylthio-fentanyl (left) and 3-methyl-thiofentanyl (right) for instance, 4-methylfentanyl, 4'-methylfentanyl and 4"-methylfentanyl are all known compounds, as are 3-methylthio-fentanyl and 3-methyl-thiofentanyl, all of which have varying potencies and pharmacokinetics. confusion between different positional isomers is especially significant in the case of fentanyls because of the huge variation in potency between different members of the class. the weakest compounds such as benzylfentanyl are around the same potency as codeine (i.e. approximately 1/10th the potency of morphine), while the strongest compounds such as carfentanil and ohmefentanil can be over 10,000x more potent than morphine, meaning there is a 100,000-fold variation in potency between the strongest and weakest fentanyl derivatives. this means that two positional isomers with the same molecular weight, which may be difficult to tell apart without detailed chemical analysis, may be hundreds or even thousands of times different in pharmacological potency. also the wide variety of substitutions that have been used on the basic fentanyl structure, each of which can either reduce or increase the potency, can be unpredictable when used in combination, so it may be impossible to estimate the likely potency of newly discovered analogues until pharmacological testing has been carried out.