*ZWITTERION* - On forming nitro intermediates

So you got a little benzaldehyde of some sort or another sitting around and you say to yourself: "damn, I'd like to lengthen that aldehyde chain, and make a terminal amine out of it so I can really cook with it!".

Well, fret no more, kitchen chemist, as ZWITTERION and RIGHT HAND MAN consulted the Great Flask and found some surprising results.

Our goal, this time, being the nitrostyrene intermediate for 2-CB, but the method is general and should apply to many other aldehydes (say, for making the TMA's).

We measured out 50g of 2,5-dimethoxybenzaldehyde, 5g of vaccum dessicated ammonium acetate, and 110g of nitromethane. The nitromethane was added to a RB flask, then the benzaldehyde with swirling, and finally the acetate. The flask was then situated in a water bath at 100C with a reflux condenser on top. This was allowed to reflux for 4 hours, or 1.5 hours longer than Shulgin specifies. At the end of this time, the flask was removed from the bath and allowed to cool. After several minutes, the contents spontaneously crystallized spectacularly into yellow-orange fluffy crystals. This was scraped out of the flask, the flask rinsed with anhydrous isopropyl alcohol and the whole mess filtered on the vacuum buchner funnel. The yield of the fairly pure nitrostyrene, after vacuum dessication, was 65g!!

Now, Shulgin starts with 100g of the benzaldehyde and gets 85g of the nitrostyrene. We started with 50g and got 65. Obviously, the reaction benefitted well from the extra time. The yield, then, was approximately 90% of the theoretical.

No, we didn't recrystallize from boiling isopropyl alcohol, because, well, why? It's a clean nitro product, and it's going to get reduced by a very specific reducing agent later on, so there.

*ZWITTERION* - On LAH Reduction of Nitro Compounds

ZWITTERION has noticed an AWFUL lot of poor information concerning the use of the infamous and oh-so-difficult to get ahold of reducing agent, Lithium Aluminum Hydride (LiAlH4, Lithium TetrahydroAluminate). Now, ZWITTERION and the RIGHT HAND MAN got together to do a little thinkin' and drinkin', mostly in the lab, and have the following observations on the myths of LAH reductions:

Myth #1 - LAH must be used under an inert atmosphere!

Wrong. If you live in particularly humid region of the planet, you may consider this somewhat truthful, but if you use LAH in an air-conditioned room, chances are the humidity isn't above 65% and is unlikely to ignite. You should take the utmost care to weigh out the necessary amount without dispersing the fine powder into the air, but no undue caution is necessary other than that. Dump immediately into THF to protect it further from atmospheric interference, and VOILLA, safe LAH ready to blow the FUCK out of some nasty old nitro groups.

Myth #2 - Once the LAH is in solution, it's totally safe!

Wrong. The nitro compound that needs to be reduced must be added SLOWLY to the THF/LAH solution. Ideally, the flask should be well CHILLED, even. Many of the nitro compounds react quite violently as they liberate the first of the 4 hydrogens off of the LAH, and this causes immense bubbling, heating, and a possible explosion. Provision MUST be made for condensing the THF vapor which inevitably forms: the best setup ZWIT has seen for this is RIGHT HAND MAN's (soon-to-be) infamous Soxhlet Addition. More on this later.

Myth #3 - LAH is *impossible* to get!

Sorta Wrong. LAH is a bitch to get, but who says you HAVE to use it? ZWITTERION's research department has alread been instructed to find alternate methods of reducing nitro compounds. One hapless soul who has actually responded already mentioned the use of Zince dissolved in concentrated HCl. ZWIT likes the sound of that one (thanks Eleusis for being a good sport for a change, you old rancid bastard). Also, you can MAKE the damn stuff, from simpler to acquire compounds. It is a somewhat of a bitch, and ZWIT has no business talking about things ZWIT hasn't done.

Now, what did ZWIT and RHM use our precious supply of LAH on? Why, reducing a Nitrostyrene to the amine, of course. There will be a separate post by ZWITTERION concerning the preparation of the Nitro compound from the benzaldehyde in which ZWIT and RHM achieved a near DOUBLING of Dr. Shulgin's yield by fucking around and letting it sit in the flask too long. Hah! ZWIT loves it when carelessness turns serendipitous.

Alright, ZWIT and RHM set out to prepare 2-CB, ala PiHKAL #20. The nitrostyrene intermediate was dissolved in THF, forming a lovely transparent orange solution. It took about 500mL of THF to dissolve 40g of the nitro compound. Next, 20g of LAH was carefully measured out and added to a 2L RB flask in which 500mL of THF resided. The LAH was added in small increments, allowing sufficient freak-out time as it bubbled and churned away. Next, a soxhlet extractor was greased up and allowed to mount the flask in a VULGAR display of lab erotica. Cold water was pumped through the allihn condenser of the soxhlet, cooling things down quite a bit. The glassware was then situated in an ice bath and magnetic stirring commenced.

After a "reasonable" period of time (approximately 2 cigarettes, 1 coke and a puff of a distinctly odiferous white powder for my compadre, RHM), The allihn condenser was removed from the soxhlet and the extraction chamber filled with THF/nitrostyrene until it just tripped the siphon tube. The condenser was quickly replaced and WHOA... What da' fuck??? That shit is BOILING like mad!

Now, kids, listen up REAL carefully, because this MAY SAVE YOUR LIFE!!!

Shulgin says to "add the nitro compound in THF solution" as if nothing major is going to happen. We added perhaps 10% of the nitro compound, AT MOST, and the reaction was quite violent and vigorous. RIGHT HAND MAN suspected this would be the case, but ZWIT was completely oblivious to the potential ferocity with which this could have reacted. Needless to say, adding the nitro compound all at one will likely result in your face disappearing all at once.

It took about an hour to finally add all of the nitro compound to the THF. In retrospect, I think a pressure equalized addition funnel might have been the best way to introduce it, since a nice slow drip could be managed resulting in less violent a reaction. Once all the compound was in, the soxhlet was replaced with a west condenser for refluxing. A drying tube was NOT mounted on the top, working on the idea that the vapor pressure of the THF would reasonably exclude water (it does). The whole setup was moved under the fume hood, and a water bath was heated to 59C where it sat and gently refluxed for 28 hours.

At the end of refluxing time, IPA, then dilute sodium hydroxide solution was added to destroy any remaining hydride and to precipitate the aluminum as insoluble aluminum hydroxide. The flask contents were then allowed to cool and filtered strenously on the vacuum buchner funnel with fast paper. The aluminum hydroxide forms a paste-like gelatin that is difficult to filter - vacuum is required.

Next, the THF/phenethylamine solution was concentrated on a rotary evaporator, though distillation would be quite acceptable (damn, rotavaps sure are nice to work with).

The yield of the crude phenethylamine was approximately 26g, beating Shulgin by a healthy margin - however, no further processing was done, which was probably an error on our part. Shulgin converts the amine to the HCl salt, washes it with methylene chloride, then converts back to the free base, extracts with methylene chloride, strips the solvent off, then distills the freebase. We looked at that mess and said "way too much mechanical loss here". It is probably a good idea to distill the freebase directly from the post-concentrated reduction solution, though. Protection of the freebase from atmospheric carbon dioxide seems like a good precaution as well. The receiving vessel should be sparged with nitrogen or helium, then the oil added until it is ready for use.

Of course, we're going to brominate that 4 position, hehe.