Summary of common mistakes in organic synthesis

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There are too many chemical experiments, and many steps involved in them; if one has not done them before, mistakes are often made. The lessons learned from these mistakes are extremely valuable. This article compiles discussions from a certain forum (name unknown) regarding mistakes made in experiments, so that others can learn from these valuable lessons and avoid repeating the same errors. 1. For reactions carried out under acidic or alkaline conditions, try to neutralize the product during post-treatment if possible. Otherwise, the product may decompose over time. 2. Here, after using up the diazomethane, we always add some acid to destroy any remaining diazomethane. One guy was bold enough to use concentrated hydrochloric acid (when dilute hydrochloric acid or acetic acid should have been used); this resulted in intense heat generation due to reaction with the remaining alkali. The ether solution of diazomethane caused an explosion as a result. Another teacher failed to apply vacuum grease to the stopper of the separatory funnel, and friction led to the ignition of the ether – it was really scary. Everyone must be extremely careful when using diazomethane; it’s best to have an experienced person around to guide you during the first attempt, and never proceed alone. Also, don’t use too large a quantity – no more than 25 grams of nitrosomethylurea at a time; if a larger amount is needed, it should be prepared in several batches. 3. Be especially careful when using ether in summer. I used ether for extraction in August this year; I just shook it gently in a separatory funnel, and just as I was about to release the gas, it exploded. Fortunately, it didn’t hurt me. My product, ah! ! ! 4. Once, while performing liquid-liquid extraction, I first washed the organic phase (containing the product) with 50 ml of HCl, and then washed the product with 50 ml of 5% NaHCO3. During shaking, the stopper was dislodged and all of the product was spilled out. . The reason is that it wasn’t deflated. Everyone must be careful when using cleaning products; if gas is generated during cleaning, it is essential to ensure that the gas is released. 5. I always find experiments troublesome and don’t like wearing rubber gloves. Due to frequent use of concentrated nitric acid and hydrogen peroxide, the skin becomes very painful; it either turns white or yellow. Especially with the recent reports about Gigeng Calcium hydrogen peroxide, I’m really scared that something might happen to me because of hydrogen peroxide as well… I hope XDJM won’t find it troublesome and will definitely take care of themselves. 6. Similar issues also need to be considered when using potassium permanganate. In the dermatology department of hospitals, potassium permanganate is often prescribed as a topical cleansing agent; its medical name is PP powder. So, this PPMM asked her boyfriend to get some from the chemistry department to use for washing… As a result, everything turned yellow and it caused a lot of pain, mainly because she used too high a concentration. Take this as a warning! ! ! 7. When I was performing vacuum distillation on a substituted phenylacetonitrile product, since some NaBr was present in the crude product and could not be completely removed, sublimation of NaBr during the distillation process likely caused the vacuum level to drop sharply after some time; I did not notice this issue at the time. So, I defeated that nearly 1kg product like that! Tragic! Therefore, it is urged that everyone be extremely careful when performing vacuum distillation. The most important thing is: do not leave during the vacuum distillation process~! It is necessary to keep an eye on changes in stress in order to take proactive measures! 8. In experiments, the amount of material added to the reaction flask must not exceed 2/3 of the volume of solvent in the flask. Once I added too much; as a result, the volume of the material increased significantly during heating, and it all spilled over, ruining my oil bath. 9. When using an aluminum-nickel alloy to add concentrated alkali for hydrogenation reduction, be sure to add it slowly! The reaction releases a large amount of heat, which can lead to boiling over or even explosions. 10. Do not use Na to remove water from DMF. Once, a colleague in our lab performed this procedure using a 5-liter flask, and as a result we got a mixture that resembled porridge; it seems the two substances reacted with each other! 11. Drying polyethylene glycol with magnesium sulfate results in a mess! ! ! 12. A colleague injured their hand with a glass sleeve handle due to excessive force; even worse, another colleague severed the tendons in their wrist while connecting tubing to a condenser – this is by no means an exaggeration; it is a bloody reality! 13. I’m not sure if everyone uses autoclaves frequently, but I personally think these devices pose a relatively high risk; it’s necessary to keep an eye on pressure changes at all times. I conducted ammonia decomposition experiments for a long time with no problems, so I became complacent. Eventually, the pressure suddenly rose to 120 kg – fortunately, there was no explosion; otherwise, I would have been in trouble. 14. When drying funnel-shaped containers or separatory funnels, it’s best to remove the piston before drying them, otherwise, due to different expansion coefficients, the piston could cause the container to burst. I ruined several constant-pressure funnels, which ended up costing my boss a lot of money. A 1000ml constant-pressure funnel costs 40 yuan. 15. After the secretary of our unit finished preparing the samples for decomposition, he failed to turn off the power supply; as a result, the place caught fire in the middle of the night, causing complete chaos and alerting the fire department. To this end, the secretary also conducted a special review. 16. Everyone still remembers the fire at Dr. Li Weidong’s laboratory, right? It was because the power to the heating element wasn’t turned off that the water dried up, the wiring of the heating element caught fire, and in the end the entire laboratory was reduced to a pile of char. 17. A few days ago, a colleague in our laboratory was working with azides; it was summer at the time, and he carried out the experiments at room temperature with no problems. But for some reason that day, just a slight shake caused an explosion that left him severely injured. Fortunately, he was wearing goggles, so the lenses broke, but his eyes weren’t damaged. 18. When using a pH meter in experiments, it’s essential to follow its operating conditions regarding temperature/humidity, etc. I remember suffering from this issue in an experiment – the analysis results were incorrect. I checked everything from the buffer solutions to the reagents, only to find out that it was simply because the weather had gotten colder. 19. An explosion-proof valve must be installed on high-pressure reactors ； For flammable and explosive gases, leak testing must be thorough (using an ‘electronic nose’) ； Do not attempt to repair electrical equipment by yourself (someone in our company almost lost their life because of this) ； Toxic experimental environments must be well-ventilated, and protective gear against toxins should be worn ； The laboratory should have good experimental habits, strict operating procedures, and an accountability system. 20. Do not forget to turn on the condensate water during distillation or rectification processes. 21. Be sure to drain all the water from the rotary evaporator before leaving; otherwise, the cold weather may cause the condensation tubes to crack. On New Year’s Day, our company scrapped quite a number of them. 22. I have seen people, after conducting an experiment on the reaction between anhydrous ethanol and sodium metal, simply pour the residues into the sink. The sodium metal that had not reacted completely came into contact with the acids remaining in the sink, resulting in an explosive reaction and a burst of fire. Fortunately, no one was injured! ! ! 23. The students in our laboratory went to have lunch, while the experiments continued over there. We planned to go there right after eating, but a classmate needed help, which delayed us; as a result, the laboratory caught fire and was completely destroyed. Thankfully, there was no explosion. Sigh, it’s still a scary experience. 24. Before using a CaCl2 desiccator, be sure to check whether it is unobstructed. It was because I didn’t conduct inspections; there were several instances of backflow, and when the temperature rose, the drying tube was pushed away by the rising hot air and exploded. 25. When one of my junior colleagues was handling silver perchlorate, a small amount remained at the mouth of the bottle; when the stopper was rubbed against it, an explosion occurred. Fortunately, the few grams of substance inside the bottle didn’t explode, otherwise he would have been hurt badly. 26. Those who work in chemical analysis often use instruments such as burettes and separatory funnels, and these devices need to be lubricated. They should be oiled from time to time. Once, I failed to apply lubricant for a long period, and when using an acid burette, the valve at the bottom couldn’t be turned properly; applying force caused it to break, and my hand was also cut. Although these are minor issues, I think it’s still important to pay attention to them. 27. At my factory, when reusing hexane, we once violated regulations by not adding a reducing agent, which resulted in an explosion in a 500-liter reactor. This explosion destroyed the entire ceiling of the workshop, and one worker was left with only a blackened spine. Remember: ethers are dangerous! 28. While preparing NaH, accidental stirring caused the bottle to break, and since there was water on the work surface, an explosion occurred immediately. It’s really very dangerous. 29. When using oxidants such as hydrogen peroxide and m-chloroperbenzoic acid, a reducing agent must be added for thorough post-treatment; otherwise, it can become extremely explosive. 30. Once, while doing an experiment, I accidentally got exposed to phenol, which caused a layer of skin to burn off – what a lesson! I also used dilute NaOH to clean the area at that time. Another time, I forgot to turn off the water, and as a result, there was water leakage the next day. 31. Once, when I was borrowing someone else’s hanging alcohol burner, I used it for an extended period of time, and the plastic tube used to deliver the alcohol (which should have been a rubber tube) caught fire at the connection point with the burner. Fortunately, there wasn’t much alcohol left; I sealed one end of the tube to prevent the alcohol from flowing out, and then used a large wet cloth to extinguish the fire. Although the problem was resolved promptly, I was still terrified. 32. Another time, while performing vacuum distillation, I failed to secure the condensation system properly, and as a result, the solvent sprayed out from the bottle’s opening; unfortunately, the product was also sprayed out! 33. LaNi5 powder that has been used in hydrogen storage tests should not be thrown directly into the trash bin, as its extremely fine particles can easily oxidize and catch fire. I have seen this happen several times in our laboratory; fortunately, there were people around, otherwise the consequences could have been disastrous. It’s best to wrap it in wet paper. 34. One of my seniors once failed to check carefully, which caused one end of the high-pressure drying tube to protrude; fortunately, no accidents occurred. I too almost destroyed a costly heating element by failing to turn off the heater after completing the experiment. 35. The format reaction requires anhydrous **furan**, dehydrated using metallic sodium. After steaming, the flask was left there for a few days; assuming that all the sodium had reacted, alcohol was not added and water was poured in directly. At first, nothing abnormal happened, but after a while, smoke began to appear... and it exploded! Fortunately, it was only a minor injury. I’m still shaken! 36. Sodium peroxide reacts with water, which can be tested using a splint with a spark. Since my personal skills in chemical experiments aren’t very good. It’s all because they want too much! I took three teaspoons of sodium peroxide, but added only a few drops of water; testing it with a splint covered in embers showed a positive result. Later, out of curiosity, I inserted a wooden stick with embers at the bottom of the test tube, and as a result—explosion! Fortunately, I chose a large, hard test tube when getting it. Otherwise, you’ll lose your life! The reason is that there is still a large amount of sodium peroxide and a small amount of oxygen at the bottom of the test tube. When a glowing splint is placed at the bottom of the test tube, carbon dioxide is produced first; this carbon dioxide then reacts with sodium peroxide to produce oxygen. The glowing splint subsequently reacts with this oxygen to produce carbon dioxide again... 37. In the past, when working with products, I often failed to pay attention to adjusting the pH level, and as a result the products wouldn’t separate. After adjusting the pH to neutral, they did separate. 38. After acid-washing the reaction mixture, if NaHCO3 is used for neutralization, it’s necessary to wash it with water first; otherwise, a large amount of gas will be generated during the separation process. 39. I was about to pour a bottle of THF that had just been received into the distillation flask containing Na beads; fortunately, a senior colleague saw this and stopped me in time. 40. I have never encountered any dangers while carrying out organic synthesis. I just remember that the disciples of one teacher all worked with phosphine-related substances; minor explosions would always occur during solvent treatment, which was quite terrifying. I want to warn those who work with phosphine to be careful. 41. Acrylic acid is also quite dangerous; last time, a junior colleague put half a bottle in a ground-glass flask and placed it in a place with strong sunlight, and it exploded, almost causing disfigurement. 42. When raising the temperature slowly, be sure not to leave it unattended – it has ruined so many of my experiments! The stoppers used for separating hot liquids in separatory funnels tend to get stuck easily; last month I broke one, and I had to apply band-aids to several places on my hand before I could continue working for another three days. 43. When carrying out organic synthesis, sometimes the final quaternization step doesn’t succeed, as the acid-base neutralization releases heat rapidly, causing foam to form. Adding an antifoaming agent at the beginning of the neutralization process proved to be effective. 44. When pressing the column, be careful to prevent the eluent from being flushed out due to excessive pressure. Especially when a leaching agent is added, 45. For hydrogenation reduction, care must be taken with palladium on carbon or Raney nickel – they should not be exposed to air. Once, while carrying out the synthesis of ephedrine, part of the palladium on carbon was exposed to air due to it being protected with ethanol, which led to combustion and an explosion. Thanks to the timely rescue, otherwise the tonnage of ethanol in the tank next to it would have led to unimaginable consequences. 46. Some time ago, a colleague failed to remove the vacuum tube in time after the pressure reduction filtration was completed; as a result, the 5000 ml two-necked flask continued to be under vacuum. About ten minutes later, there was a loud ‘pop’ sound, and the flask exploded, spilling DMF everywhere, including all over my boss’s head. Fortunately, no one was around at the time; otherwise... . . So after the vacuum filtration is complete, be sure to remove that tube! ! ! 47. Attention should also be paid when nitrating food samples; generally, a mixed acid of sulfuric acid, nitric acid, and perchloric acid is used for digestion. The digestion process does not need to be rushed, as otherwise explosions may occur when dealing with large quantities of starchy samples. I have encountered such a problem before. 48. When I was first doing experiments, I remember it was related to sodium alkoxides; when a piece of sodium was added, one piece accidentally fell into the water bath. The sodium started burning in the water and moved around, and I thought an explosion was going to happen. Thankfully nothing happened, but it scared me to death. 49. The Fuchs–Gocke reaction was carried out using anhydrous aluminum chloride as a catalyst, with recycled water being used to absorb the hydrogen chloride produced. Once the reaction was complete, cooling took place, with the temperature dropping from 80 degrees to 40 degrees. Since the water wasn’t drained in time, it flowed back into the mixture, causing everything to be flushed up to the ceiling – it was quite scary! It’s still terrifying when I think about it. Everyone should be careful to avoid situations where negative pressure occurs. 50. Let me add a few words as well. I’ve been conducting synthesis experiments for two weeks now, following the procedures described in the literature. However, the literature only mentioned four words regarding the post-processing of the product: “precipitation with ethanol.” To remove the product from a pH level above 14 as well as NaCl, I had to conduct some preliminary experiments first. At first, I thought that just ethanol would be sufficient, so I added lots of ethanol, working hard in the process; I wasted 5–6 bottles of anhydrous ethanol yet still couldn’t lower the pH value. Eventually, even NaCl proved ineffective. Then I thought about it: if precipitation is involved, then it must be done using anhydrous ethanol. But in what solution should it be dissolved in order for precipitation to occur? That’s when I realized that I needed to keep adding water followed by ethanol in order to achieve the desired result. The soluble B-cyclodextrin product is highly soluble in water but precipitates immediately in ethanol, becoming very sticky. However, after adding more ethanol and stirring for a while, it loses its stickiness, and particles that are no longer sticky appear, allowing them to be filtered out to obtain the product. So, one needs to be patient and repeat the experiments described in the literature, as well as carefully consider all the details, precautions, and conditions involved or hidden therein; only in this way can one carry out one’s experiments successfully. 51. After carrying out the above post-treatment steps, it’s also necessary to recycle the large amount of anhydrous ethanol that was used. Let me tell you – I used 30 bottles of it. If all of that were discarded, my boss would definitely scold me severely. So I forced myself to carry out vacuum distillation. Before, I would only concentrate a small amount of the product, adding no more than half of the capacity of the pear-shaped distillation flask at a time. But this time it’s different; with 30 bottles involved, it will take a long time to complete the process. Moreover, our laboratory only has 500ml flasks, so we can only recover 250 ml each time. This is due both to the number of times distillation needs to be performed and to the fact that each distillation session takes 20–30 minutes. I used a circulating water vacuum pump and heated the mixture to 60 degrees Celsius. I’m so tired. Although it took two or three days, during that time I carried out other synthesis experiments, wrote experiment reports, and organized my thoughts on the recent experiments. I also recovered over 100 silica gel plates that had been used for TLC. Most importantly, I was able to recover ethanol and ensure its purity; sometimes I distilled too much of it, which caused boiling over and contamination of the reflux condenser channel, so I had to distill it 2–3 times or rinse it with distilled water in order to recover the ethanol. What I want to say is that when conducting experiments, one should always have the experimental habit of recovering products, solvents, and raw materials. 52. Today I saw sodium amide; the manual says it is green, but what I saw was white (the surface absorbed moisture and turned into sodium hydroxide, which then reacted with carbon dioxide to form sodium carbonate). It was as hard as stone, and it took me a long time using an iron stand to break it apart. Due to the increased surface area and its reaction with the moisture in the air, it burned me to death. At first I didn’t wear gloves, so my hands got dirty, but I wiped it off right away and nothing happened. 53. When treating anhydrous aluminum trichloride, the gas produced upon contact with water is HCl. Be careful! I was in a hurry to leave that time and added water too quickly; fortunately, I was working in a fume hood, otherwise the protective glass would have been covered in a sticky residue. My face is ruined. 54. When using a new pipette, was it washed with distilled water? And when taking samples, was the pipette rinsed with the sample? ? 55. When preparing drugs that release heat easily (such as NaOH solution), is the volume adjustment carried out at room temperature? ? 56. I remember once using a heating element to provide a water bath for heating; the junction thermometer was set at 50 degrees. I left the lab at noon while it was still running, and in the afternoon a teacher told me that the water in the bath had evaporated. As a result, the heating element suffered a short circuit. Fortunately, the electrical system in the lab was in fairly good condition, so the circuit breaker tripped, preventing any serious problems from occurring. It is therefore concluded that for long-term heating, an oil bath is the best option, but someone must be present to monitor it when using an oil bath. Several graduate students from the School of Chemical Engineering in our university had experiments go wrong multiple times because they left the laboratory while using an oil bath for heating at noon; as a result, the oil caught fire and caused a blaze. For this reason, the School of Chemical Engineering has already expelled several students. 57. I conducted an experiment yesterday: it involved a reaction between two solids. At first, I didn’t realize there was any danger involved, but later our teacher said that such reactions can easily lead to explosions. One of the reactants I used was NaH; although the process itself wasn’t dangerous, thinking about it now still makes me a little scared. I was the only one there at the time, and to put it bluntly, what if something had gone wrong? Also, during summer, it’s important to turn off the power supply and unplug the devices after conducting experiments. Several of my instruments have broken down now and are no longer functional, which wastes time. After reading all these examples, I believe anyone who has read them must have many thoughts. Therefore, the most important thing is to develop good experimental and hygiene habits, to protect oneself and others, and to avoid causing harm to others or to oneself!