We’re attempting our first multi-step synthesis and have finally gotten off the chalkboard, out of the notebook, and into the lab. We’re starting with a small 500mg pilot reaction to make sure everything is in working order before we scale up. As all of the reagents are being paid for out of pocket, mistakes and wasted reagents can become costly!
Acylation is a standard orgo 1 or 2 lab experiment, but doing something on paper is different than in a round bottom flask. The arrival of our acyl halide made moving forward with the (hopefully) 5′ acylation of Meldrum’s acid a possibility. Not wanting to dump our entire 25g ($40) of Meldrum’s acid in a RBF and go with the literature procedure, we decided to try it out ourselves on a small scale.
We started with 500mg of the recrystalized (from acetone) Meldrum’s acid dissolved in 2mL of DCM which had previously been dried over sodium sulfate. We followed that with 4 eq of pyridine which were added in 200uL batches over a period of about 10 minutes. Since everything was done on such a small scale, we did not use addition funnels, as adding 700uL of a reagent over 10 minutes would be futile using large glassware. Instead, we opted for small additions using a p1000 micro pipette, which seemed to work ok.
Our Schlenk line was not setup, and the nitrogen gas wasn’t delivered on time, so we weren’t able to run the reaction under nitrogen like we wanted to. While not absolutely necessary, it could theoretically improve yields by keeping moister out of the reaction container, which would quickly eat up our acyl halide.
An equimolar equivalence of our acyl halide was added to the reaction after being diluted 4x in dry DCM. Upon addition of the first small batch of acyl halide, the reaction turns yellowish orange as expected. Small partitions of 200uL of the acyl halide in DCM are slowly added to the reaction mixture over a period of about 45 minutes, and the solution starts to turn darker orange, then deep red/purple.
After the acyl halide was completely added, the reaction mixture stirred for another 30 minutes on ice, then was removed from the ice bath and allowed to stir at room temperature for another 30 minutes. The reaction mixture was then quenched with 20mL of 2N HCl and the organic layer was removed in a sep funnel. The aqueous layer was extracted 2x with DCM and the organic layer and DCM extracts were combined. The combined organic layers were washed with 2N HCl and then with saturated NaCl solution.
They were dried over anhydrous sodium sulfate to yield an orange solution, and excess solvent was removed by rotary evaporation to yield a deep red/orange oil.
TLC was done throughout the reaction, though trying to take pictures of them under UV light was kind of a pain. We’ll need to develop them with iodine in the future, especially since the acyl halide might not be visible with just UV as any unreacted acyl halide will probably convert to the carboxylic acid upon touching the silica or just atmospheric moisture. Hopefully when the NMR is up and running we can make use of though. I’d like to trust the FTIR we have but…I’m unsure of how accurate it is.
The big dot all the way to the left is the Meldrum’s acid standard. The 2nd column is half way through the reaction with 0.5eq Acyl halide added, you can see a dot slightly above the Meldrum’s acid and then a dot town towards the bottom. The 3rd column is the final extracted and rotovapped product. Since we’re adding a pretty decent sized alkyl chain, I was thinking the product would be more soluble in the mobile phase, and give a higher spot on the TLC. You can maybe see that the large dot in the final column is indeed higher than the Meldrum’s acid standard…but I’m not that comfortable in determining the success of the reaction via TLC. I’ll be happy with a decent NMR, though I’d really like to just be able to fly it in an LCMS.
A lot learned and a lot to learn, I’ll try to make picture quality and video quality better in the future, but I was just in a hurry to get going as I’m sick of waiting around for things. Take action every day!