-----BEGIN PGP SIGNED MESSAGE----- Hash: SHA512 Alpha-pyrrolidinovalerophenone synthesis by def 2025-09-09 These are unnecessarily verbose lab notes of my a-PVP synthesis experiments. Ordinarily, lab notes and chemistry writeups are concise and to-the-point because they are inteded to be read by other experts in the field. This writeup is geared towards those who are not such experts and can thus benefit from the extra explanations and unnecessary context given throughout the text. 0. Ventilated area (fume hood, balcony or outside) is recommended unless you enjoy smelling nasty irritating chemicals that can make you feel ill and cause headaches among other symptoms. Fortunately, the chemicals used in the synthesis are known to be relatively non-toxic to humans even with high exposure levels (the only exception being 2-bromo-valerophenone whose toxicity profile is unclear due to the lack of studies). Nitrile gloves and PPE are highly recommended to avoid chemical burns and protect eyes from corrosive chemicals such as strong acids and bases. 1. Add 157g 2-bromo-valerophenone (n = 0.65mol) and ~300mL of EtOAc, xylene or benzene as the reaction solvent into a 1L round-bottom flask reactor. Fuck, even acetone works somewhat but creates annoying emulsions that can be painful to handle later on. 2. Load 94g pyrrolidine (81mL, 2.5 mol eq) to a pressure equalizing addition funnel. 3. Start dropwise addition with *vigorous* stirring (maintain temp below 65C). Practice has shown that vigorous stirring is crucial if using xylene as the solvent for n > 0.5 mol scales because some white junk can precipitate out of the solution with slow stirring. If that happens, shaking the reaction mixture violently (for example, in a separatory funnel or in a boiling flask closed with a glass stopper) usually dissolves the precipitate. Interestingly, increasing the volume of xylene does not seem to prevent the precipitation. Fortunately, the precipitation does not seem to affect the final yield in any way so, in principle, it can probably be safely ignored (although it can cause issues if the magnetic stirrer gets stuck in the precipitated junk). 4. Run the reaction for 30min after addition of the last drop. We do not have to wait for hours or overnight for the reaction to finish because of the large excess of pyrrolidine used (2.5 molar equivalents). It is possible to use less pyrrolidine (for example, 1.5 mol eq.) but then the reaction slows down and a reaction time of 12-36 hours is recommended. 5. Wash the reaction mixture with saturated sodium bicarb water (2 x 100mL). This removes lots of impurities from the reaction mixture and, most notably, NaHCO3 also helps to neutralize bromine released by the Sn2 substitution reaction. Bromine is toxic to humans and spilling it down in the drain can damage pipes and the sewer system in general. Properly neutralized bromine is harmless and can be safely poured down the drain. Sodium thiosulfate (Na2S2O3) is a great neutralizing agent for bromine. 6. Acidify with 72g (61mL) 33% HCl (citric acid and H3PO4 work as well). Anhydrous acids should be dissolved into a small amount of water (~150mL) before adding to the reaction mixture. After the addition of the acid, stir for a while and then stop so that the solution separates into two layers. The bottom layer is the acidic aqueous layer containing a-PVP. Thus, save the bottom layer for further processing and discard the top organic layer consisting mostly of our reaction solvent (EtOAc, xylene or whatever) and minor impurities. 7. Basify the aqueous layer with 75g NaOH dissolved in a water Note that citric acid and H3PO4 added in the previous step are triprotic and, therefore, 3 molar equivalents are required to raise the pH enough to create an oily a-PVP freebase layer on top of the aqueous layer. Moreover, NaOH can be replaced basically with any strong enough base. For example, Na2CO3 ("soda ash") is suitable (and arguably even better because it is "milder" and seems to give an endothermic reaction producing less byproducts and impurities) but it requires a little more care because of the released CO2(g) which can build up pressure inside closed glassware systems. 8. Decant the top freebase layer discarding the bottom aqueous layer. The freebase is not pure enough for ingesting assuming one is a responsible person and not a retarded addict. The freebase is, of course, psychoactive and can be ingested, for example, by smoking or taking it orally. However, please do not be so desperate as the crude freebase contains significant amounts of non-polar solvents in addition to various impurities. If one really wish to experience a-PVP in its freebase form, simply start with a pure a-PVP HCl sample and basify it and go on from there (or just trust me, a-PVP freebase is not better in any way but smells and tastes incredibly disgusting). 9. Add HCl(aq) to the a-PVP freebase until the pH reaches 5-6 (~66ml 33% HCl). Make sure to not overshoot and make the solution too acidic (pH 2-3) since it can prevent a-PVP crystallizing out of the solution. Correct overshooted pH with preferably a-PVP or increasing the volume with acetone, but if this is not sufficient try adding a miniscule amount of NaOH. 10. Increase the total volume to 1L by adding acetone and put the a-PVP/acetone solution in a freezer. Wait preferably for ~12-24h so that a-PVP crystals precipitate out of the solution (while any impurities remain dissolved in the acetone). However, often most of the product crashes out of the solution within the first couple of hours. The crystallization can also be forced to happen immediately by using freezing-cold HCl(aq), a-PVP freebase and acetone (taken straight out of a freezer) in this and the previous steps. In fact, this eliminates the need of pH measurements as the crystals simply stop forming after the target pH range (5-6) is reached. 12. Filter a-PVP crystals out of the solution (coffee filter works just fine). 13. Dry the (wet) a-PVP crystals in a room with good ventilation. 14. Recrystallize in acetone (and/or EtOH/IPA:H2O) to obtain pure white powdery product. This is unnecessary unless the product is clearly discolored or otherwise dirty. 15. For big chunky crystals, perform a slow evaporation (in EtOH:H2O solvent) over several days. This is purely cosmetic and does not improve the quality of the end product. Yield: ~125g a-PVP HCl (70%) -----BEGIN PGP SIGNATURE----- iHUEARYKAB0WIQRRfNzxkhGCNUJHauoZ/qATiDeBBAUCaMAdzAAKCRAZ/qATiDeB BJs8AP4/ZJkP4AducLVMfItlpVYZEYH6AzQ/HQnhu3EkoNQvegEAo+1CoKfQ3dY6 66eV0cK+yl5i5c9nnl8P5b39eOgYqwY= =2Ize -----END PGP SIGNATURE-----