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             Reductive Amination of MDP2P with Al/Hg + Nitromethane
                                 by Methyl Man
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Since the appearance of Ritter's writeup of this method in Total Synthesis II,
much discussion has taken place about it but, it has sometimes seemed, little
has been clarified. This is due in large measure to the sensitivity of this
reaction to even the most minor changes in its many variables. With this
writeup, I hope to provide a clearer view of the method and to allow others to
benefit from the hard-won experience of someone (not me) whom we'll call Mr. A.
Ritter's original writeup, while inspiring, lacked details about the many
nuances that, once understood, allow the amateur chemist to really understand
this reaction's dynamics. Thus I have tried with this writeup to help the
neophyte who has only physical observations and scant written material to guide
him (although I suspect and hope that it may even help a few more seasoned cooks
as well).

The first thing I'd like you to look at is the array of interrelating variables
in this reaction that make it so delicate. They are as follows:

1) the thickness/type of the aluminum
2) the consistency (i.e. flat, ground, etc.)
3) the amount of HgCl2 used in relation to the amount of aluminum
4) the addition rate of the MeNO2/MDP-2-P
5) the size of the reaction vessel in relation to the scale of the reaction
6) the ability to effectively stir the reaction
7) the coldness of the water through the reflux condenser (yes, even that!)

The above factors are sort of submitted in an order of importance (#1 being most
important), but in reality they are all inextricably related. I observed
firsthand the trials and tribulations of Mr. A as he struggled to match up the
correct combination of ratios and conditions that would allow a smooth,
consistent reaction and predictable results every time. Finally, after lots of
frustration, confusion, losses, and---in the end---a revelation, the perfect set
of elements was hit upon and recorded.

The scale Mr. A chooses to perform this reaction on is half-scale to the scale
in the Ritter writeup, which was 55g aluminum and 50g MDP-2-P. Therefore this
writeup will illustrate the reaction on a scale of 27.5g aluminum and 25g
MDP-2-P. The subject found for his own personal reasons that this smaller scale
was much easier to manage (not the least of which is that even with a huge
4-liter separatory funnel, at this smaller scale it gets pretty filled up!).
There's no doubt that the original larger scale can be successfully applied,
although it would require adjustments in the glassware capacity, stirring
method, and probably other elements.

MATERIALS and APPARATUS:

* 27.5g Reynolds Wrap Heavy Duty aluminum foil
* 25g MDP-2-P
* 20 mL MeNO2 of 99+% purity
* 750 mL MeOH + 50 mL more for addition funnel
  + additional small amounts that will be needed later to thin the mixture
* 400mg HgCl2
* 2-liter 2-neck flat bottom flask
* reflux condenser (400mm preferable)
* 250mL or 500mL addition or separatory funnel
* cooling setup (bucket, water pump, tubing, 1 bag ice)

METHOD:

1. Weigh 27.5g of Reynolds Wrap Heavy Duty aluminum foil (NOTE: it HAS to be
   Reynolds and it MUST be the heavy duty stuff) and then tear it by hand or cut
   it with scissors into small rectangles approximately 1" by .75". Settle down
   with this task with a good CD or TV show because it is tedious and will take
   about 30-40 minutes.

2. With a coffee grinder, "grind" these pieces of foil for durations of about
   10 seconds. Fill the coffee grinder only loosely (about two thirds full -
   don't stuff it! That will adversely change the consistency of the ground
   foil). It will probably take about 4 to 5 "loads" in your grinder to do the
   whole 25g of foil, depending on the size of your grinder. (In actuality, the
   foil does not get "ground," but rather, each individual piece just gets
   compacted and compressed. If it is compressed too heavily, the inner surfaces
   of the foil nuggets may be rendered inaccessible to the Hg/MeOH solution,
   changing the timing of the amalgamation and maybe even causing an incomplete
   or failed reaction.) When properly done, the foil should be in gnarled little
   nuggets about the size of sunflower seeds (shell included) and should NOT
   look super-tight and small.

3. Place a 3" stirbar in your 2L flat bottom flask and onto your stirplate. Add
   the foil nuggets to the flask and then proceed to set up your glass, support
   and clamps so that the reflux condenser and addition/sep funnel are securely
   affixed and your flask is well-centered on the stirplate (this will be
   critical when you begin to attempt stirring!). Also, prepare your cooling,
   i.e. attach the inflow and outflow tubes to the reflux condenser.

4. Carefully add the 400mg HgCl2 to 750mL MeOH to a tightly sealable bottle and
   shake to dissolve all HgCl2. Set this solution aside.

5. Combine the 25g MDP-2-P, 20mL MeNO2, and 50mL MeOH and pour them into the
   addition/sep funnel. Rinse your beaker (or whatever you used) with a tiny bit
   of additional MeOH to get the residual ketone and add it to this
   MDP-2-P/MeNO2/MeOH solution.

6. Very slowly and carefully (w/gloves, glasses, long sleeves and a Hail Mary if
   you're Catholic), using a large funnel, pour the HgCl2/MeOH solution from
   step 4 down the condenser.

7. Turn the stirring on full blast for a 5-second burst to intimately mix the
   solution and the foil. If you have prepared the foil as described above, it
   will easily stir. Give it a few more 5-second stirs over the next few
   minutes. I believe that doing this really helps facilitate the amalgamation
   process that is about to occur.

8. After about 5 minutes or so, you will begin to see bubbles popping up on the
   surface of the MeOH solution. At first they will be tiny, like champagne
   bubbles. Then after a few minutes you will see them joined by larger bubbles
   closer to the size of those seen in boiling water. It is around this same
   time that the appearance of the aluminum will change from its normal shiny
   silver color and start to take on a dull gray look, accompanied by a gray
   cloudy look that begins forming in the MeOH. This is the magic moment when
   you want to begin dripping in your MDP-2-P/MeNO2/MeOH mixture. Set a drip
   rate of approximately 1 drop per second at this point and no faster. You can
   speed it up a bit later to accelerate the reaction if desired.

9. Place about 3 lbs ice into your bucket. When you can feel exothermic warmth
   begin by feeling the outside of the flask, quickly add about 2.5 liters water
   to the bucket (or an appropriate amount to make very ice-heavy ice water) and
   plug in the pump.

10. While monitoring the growing intensity of the bubbling amalgamation, turn
    on/off the stirring intermittently as you did earlier. This time it is to
    assure distribution of the added ketone/nitromethane in the reaction flask
    but also because the amalgamation seems to gain its vital momentum more
    effectively if given some significant blocks of time (meaning about 30 sec
    at a time) in between "stirring bursts." When the reaction is clearly
    starting to get vigorous and hot, crank the stirring to 10 and leave it on.

NOTE: This is where you can take advantage of Mr. A's trial and error regarding
      this reaction's parameters. If you used the kind of foil specified,
      prepared it as specified, used no more than the specified 400mg HgCl2, and
      used a 2-liter and NOT a smaller flask, you can breathe easy knowing that
      the reaction is going to hum along nicely but will not get out of control,
      and will result in perfectly processed aluminum amalgam sludge. You may
      think that a 2-liter flask is oversized for this reaction, but that is
      precisely the point. The extra headroom in the glass provides a nice zone
      of "breathing room" for the reaction and facilitates good refluxing. I've
      seen this reaction get out of hand in a 1000mL flask, and it isn't pretty,
      believe me. Use the 2-liter.

11. As the reaction progresses only a few minutes after the addition was
    started, you will observe that the aluminum is breaking up fairly rapidly.
    This is good, as long as you have the ketone/nitro mixture dripping in at a
    good rate of about 1drop per second. But be careful with the addition rate
    at this point, as a rate that is much faster than this could easily send the
    reaction into overdrive (not good). Your reflux should be unnervingly
    vigorous as the amalgamation really starts to pick up speed, with the MeOH
    literally pouring down out of the condenser. I know it's hard to believe,
    but this is what you want, this is good. I'm telling you, LOTS of trial and
    error came before this writeup. Trust me. You will also see sludge already
    starting to settle at the bottom and forming a ring on the glass around the
    top surface of the spinning mess. The consistency will get thicker by the
    minute. Add more ice to your bucket as needed.

12. At this point you can sort of control the reaction rate by slowing down or
    speeding up the addition rate a bit. Of course the reaction is already
    barreling along, so you won't want to speed it up much. The concept here is
    that you want the addition of the ketone/nitromethane to be paced
    neck-and-neck, as it were, with the breakdown of the foil as it amalgamates
    and gets turned into sludge. In other words, you have to watch those two
    things and sort of adjust the addition so that they proceed at approximately
    the same rate. It's tricky, and imprecise, but with a little experience and
    intuition you'll get the hang of it. Sure, you could be lazy and just leave
    the addition at a steady 1 drop/second the whole time, but if the amalgam-
    ation peters out way before your addition is finished, and you find yourself
    adding your beautiful ketone to impotent sludge, don't cry to me. The
    addition should take about 40-45 minutes in total, and as it's finishing,
    the state of the aluminum should be about 95% broken down. In fact the
    reaction should by now (~45 minutes after addition was started) look like a
    really thick, steely-gray chowder with only minor small slivers of
    undissolved aluminum visible if any at all. You will probably even need to
    add an extra 20-30mL of MeOH down the condenser at this point (or before) to
    help it keep stirring effectively. This is no problem.

A note about color at this point is helpful too. Comparing successful reactions
to failed ones, I have observed that there is a distinctive color to the mixture
early on that indicates healthy amalgamation and foretells a successful run. At
a point maybe 30 minutes or so post-addition, the reaction takes on a color that
I would describe as being "light steely gray with blue overtones." It is a hard
thing to describe shades of gray, but I will try. It is a light shade, akin to
the color of common gray sweat pants, but I'd say with a very slight suggestion
of a blue hue in there as well. This is in contrast to what I saw in failures
resulting from using too thick of aluminum and not enough HgCl2, where a dark
metallic gray with definite green overtones (from unreacted ketone) was noted.

NOTE: Another point I would like to make about the timing of the addition
      against the breakdown of the aluminum is that Mr. A found that there was
      a definite "spike" curve to the amalgamation reaction which was easily
      observed by watching the reflux rate. That is to say, there is a peak
      that it builds up to and then comes down from. At this scale, and using
      the exact materials described herein, that buildup to peak and subsequent
      slowdown occurs over approximately 25 minutes or so---very fast. So at
      only about 20-25 minutes after you first started feeling the amalgamation
      heating up, it will have slowed to a reflux of about 2 drops per second,
      after having been at a peak with a reflux rate so furious it is a stream,
      not drops. At one hour and 15 minutes after you first started the
      addition, the reflux will have slowed to a very calm 1 drop per 2 seconds
      or so. Finally, when...

      A) the reflux has slowed to almost no reflux at all
      B) if you stop the stirring you do not see any small bubbles anymore
      C) no "uneaten" aluminum is visible and the solution is a thick, uniform
         gray soup,

      ...the reaction has essentially finished. It will reach this state at
      about one hour 45 minutes to two hours after addition was started.
      Nevertheless, you will leave it stirring happily for a total of three
      hours after the addition was finished to assure that the reaction has run
      its full course and the conversions that you desire have had ample time to
      take place. You could add a bit of external heat at this point but it's
      probably not even needed (Mr. A does it just to be sure). One reason I
      bring this all up is that there has been lots of talk about how this
      reaction needs 8 hours or 24 hours or even 36 hours to run! But those time
      frames apply only in cases where much thicker aluminum is used, and/or in
      variations using methylamine and not nitromethane. Mr. A was never
      successful in using thicker aluminum, and doesn't want to be! Why would
      someone want to make a reaction take any more time than it needs? Beats
      me! I'm mystified! The approach illustrated in this writeup optimizes this
      reaction to finish in 3 hours 45 minutes from beginning to end, and it
      probably doesn't even need that much time.

13. If you chose to apply external heat, turn it off at 30 minutes before the
    targeted finish time. Otherwise you will have to wait an extra 30 minutes
    for it to cool for the next steps.

14. When finish time has arrived, dismantle your setup, set aside your reaction
    flask, and make 750 mL of a 35% NaOH solution (750 mL H2O + 262.5g NaOH) and
    let it cool to room temp or below (safety glasses!).

15. Into a separatory funnel no smaller than 2000mL capacity, pour your nice
    gray reaction mixture, being very careful to KEEP THE STIRBAR FROM FALLING
    IN to the sep funnel and breaking it (that would be ugly). If your mixture
    is really thick, you may need to add small amounts of MeOH to thin it to a
    pourable consistency. This is perfectly fine. Wash the final residue out of
    the reaction flask with a few mLs of MeOH and add it to the funnel also.

16. Slowly pour the NaOH solution into the sep funnel (gloves and glasses! no
    excuses!). That's right, don't dump it in wholesale. Basifying should be a
    gentle process. If you bully those molecules they may decide they're being
    disrespected and choose not to cooperate. Adding the NaOH will cause the
    mixture to warm up a bit as the very last bits of the aluminum are dissolved,
    which is fine. Swirl it a couple times and give it about 10 minutes to cool
    down to something closer to ambient temperature. That yummy stinky
    methylamine smell tells you that the reaction was successful.

17. When the mixture in the sep funnel has cooled down, extract it once with
    400mL toluene followed by once with 100mL toluene. These are the critical
    moments for your yield now, so you be sure to shake long and hard (at least
    3 min) during these extractions (I don't have to tell you to vent doI?!).
    The toluene/product layer will of course be on top since toluene floats on
    water. Also, be sure to give the separations ample time to happen (at least
    15 min); it is easy to tell when it's okay to separate because the interface
    of small toluene bubbles finally resolves and you have a nice clean line
    between the layers. If you like, do as Mr. A does and finish off with a
    final small extraction of 50-60 mL toluene just to get the last of the stuff.

NOTE: Your extractions will contain a tiny amount of the base/metal/garbage from
      the bottom layer; this is inevitable but easily worked around in this way:
      when you have collected your combined toluene/product extractions in a
      bottle, chill that bottle in the freezer for 30 minutes or so. When cold,
      the garbage gets a lot less mobile and it is easy to decant the toluene
      away from it. Just be vigilant while pouring the last 50 mL or so and
      avoid letting that glob of crap rejoin the toluene. Yeah, you will lose
      the very last 2 or 3 mL, but that's life. Alternatively, you could filter
      it through a paper towel, but you will still lose the same amount when the
      towel absorbs it. Just get over it and move on!

18. If you haven't already, drain the garbage layer out of your sep funnel into
    a storage bottle or something, and wash the garbage residue out your sep
    funnel with water.

19. Wash the toluene/product 4 times (or more) in your sep funnel with 400 or
    500mL H2O and a final time with 500mL of a saturated NaCl solution to remove
    any traces of solvated HgCl2.

20. Dry your toluene/product solution with 30g of your favorite drying agent
    (MgSO4 recommended) in an acetone-cleaned, heat-dried bottle for no less
    than 30 minutes (Mr. A is superstitious so he lets it sit for an hour).
    Shake it a few times during this period.

21. Filter the solution and gas it with that good ol' HCl bubbler setup. Be
    smart and use just enough muriatic (31% HCl) to wet the salt but not enough
    to make any puddles, and put a wad of drying agent wrapped in tissue paper
    in line somehow between the reaction flask and the tube leading to your
    pipette end. Weep with joy as a bumper crop of white precipitate crashes out
    of solution.

Expected yield: approximately 20-21.5g raw odoriferous product that will purify
via careful recrystallization to 17-18g of beautiful snow-white MDMA! Ain't life
grand?

One thing that I want to mention in hindsight here since I know it's probably
going to come up, is the issue of added water.

It's been emphatically stated several times that some water is needed in this
reaction for imine formation etc. etc. That may be true, but I know for a fact
that it doesn't need to be added. That is to say, maybe there is some trace
water in the MeOH Mr. A uses (Heet) that is fulfilling this function, and maybe
it's even in all MeOH except expensive absolute anhydrous stuff. I don't know.
But he doesn't add it anymore and it definitely doesn't hurt anything.

Before, Mr. A was adding about 25 mL, and maybe it was not a good thing. But he
likes how it's going now.

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