Whew!
SWIA is breathing a huge sigh of relief. He panicked too soon. This story has a happy ending.
Final results: 1.0x of ketone yielded 1.0166x of distilled base, a 93.7% yield.
The reason SWIA was worried was because the freebase didn’t look right. Turns out it was super clean. Yield of base was high and very nice appearance of hydrochloride. And no brown tar after base distillation. One rinse with hot water and the RB flask was clean. That, in and of itself, was fucking amazing.
Oh, and the aliquot that did not crystallize and which made him come to me in a panic and ask Hive for help?--it was SWIA’s mistake, not enough acid addition (he used quick salt and sulfuric method to make direct addition acid and save time on glassware setting up--his mistake--lots of bubbles, but little acid--he vows only to use my tried and true method, as posted on Rhodium’s page. Anyway, after adding more acid, left overnight in freezer, and voila-- aliquot of 1x grams of base yielded 1.145x grams hydrochloride, a 96.5% conversion. The remainder can be recovered from acetone/IPA as base (there is always residual product that can be recovered from acetone).
Since neither SWIA nor I do anything harder these days than a cup of tea, a sample given to a buddy was confirmed to be the desired compound, yes sir!
Why was base different this time? Why so clean?
Two main things were done differently from LaBTop’s writeup of reductive amination.
1. No dessicant was added to remove water before, during, or after imine formation. -15ºC ketone was slowly dripped into equally cold MeOH/ MeNH2 solution and allowed to stir without cooling for 3 hours, temp never went beyond 5ºC. (Literature suggests that keeping the solution below the boiling point of primary amine increases formation of imine-- who knows?, maybe there’s something to it.) Cooling was applied to the reactor and NaBH4 was added every time temp came down to 9ºC and temp never increased beyond 15ºC. This took 4 hours. Contents allowed to react for 35 hours at 15ºC with stirring after last borohydride addition. Contents remained greenish, yellow lemonade color, not brown. Molar ratio ketone : MeNH2 : NaBH4 was 1: 1.2: 0.47. MeOH was three times weight of ketone.
2. MeOH was distilled off prior to water addition. I believe this to be an important factor in high yield of base, because base is soluble in MeOH and IMHO some base will always stay in solution no matter how much water is added. Besides--distilling MeOH while playing poker on the computer is a hell of lot easier than manipulating lots of stinking water/MeNH2/MeOH/NaOH/base solution and separating the desired product from the rest of the solution. A whole lot easier. Plus it is my opinion that valuable product is thrown away as long as MeOH is present in the wash water. And the amount of NaOH that must be added when flooding the reaction contents with MeOH present may affect the product and cause some of the polymerization that seems to cause the residual tar upon distillation. SWIA has always flooded the reaction contents, then last time he partially distilled MeOH and found that yield improved. This time, removing absolutely all MeOH, yield is approaching quantitative. After MeOH is removed, then base is washed with a reasonable amount of water, then NaOH, DCM added. The volume of water is reduced by a tenth and NaOH becomes almost insignificant compared to how much must be used when MeOH is present. I have read the debate as to which is easier: removing MeOH first, or flooding reaction contents with a large volume of water. I vote for removing MeOH first. Besides being easier, the yield is higher.
Remaining contents washed with water twice and separated. Wash water treated with very little NaOH and normal amount of DCM for the volume of water. The DCM/base was distilled apart from main batch. The main batch of base was distilled, and you should have seen SWIA sweating bullets, because it came over crystal clear, like water, not yellowish, as has been his experience when doing A/B workup, a la LaBTop. Base came over at 103ºC at stillhead. (Decent vacuum.) He thought something was wrong, but what a surprise when sample crystallized. Beautiful white crystals. Almost stoichiometric conversion of base to hydrochloride, with the difference to be recovered, as usual, from mother and wash liquors.
Thanks go PolySam and terbium for calming posts. terbium is right, as always--this is a reaction that’s hard to screw up. And this ketone is one tough molecule--still good after 9 months and room temp storage.
Sorry for the panic. I thank the Hive mavens (LaBTop, terbium, PolySam, etc) for responding to my post. I’m sure most of you have gone through the same thing when something doesn’t look right. Especially when stakes are high. I guess it’s human nature to doubt, thinking something must have gone wrong, when if we would just wait, have patience and confidence in ourselves, take it step by step, and reserve judgment until the job is over, we might be surprised at the positive results.
What a shame to have recently sworn off booze and coke: now would be a perfect time to pop a magnum of Dom Perignon and celebrate. Oh well, somebody, somewhere, have a drink in my name.
Regards
Argox
Disclaimer: No quantities are given or implied by anything here. I am relating a story told to me by SWIA about how he experimented with synthesizing a small amount of a commonly available substance for personal use. In this country, minimal amounts for personal use are tolerated.
