Along with the improved NBS bromination, here is an improvement to the NaBH4/ CuCl2 reduction. Scale is about 100 g, but this should work well even at 200 g+ in a 10L 3-neck flask:
1) Will use about
13 x of liquid to the 2,5-Dimethoxynitrostyrene amount. Start with
91.5 g or
0.437 mol. of once recrystallized
nitrosyrene, they are those distinctive orange hairs, but not entirely pure. A mixed bag.
2) Plan to use a total of
7.5 mol. eq. of NaBH4 or 3.278 mol or about
120g NaBH4 in total. But
100 g to dissolve now and 20g to leave out before addition of CuCl2.
3) Into a 6 L 3-neck flask pour
550 mL dH2O and 700 mL IPA. The proportion is not 1:1 water, IPA. But it is much more water, the borohydride still dissolves, and we end up working with a more convenient smaller IPA layer than the usual 2:1.
4) It is better to cool everything before adding the NaBH4. Use a bucket with
salt-ice-water cooling or even a large glass dish. Ice water cooling is entirely sufficient at this scale.
5) Add 100 g of finely crushed NaBH4, as the vessel had not cooled sufficiently it starts reacting with the water. Eventually I cool it down to about 8° C and only then begin addition of the nitrostyrene with overhead stirring at 220 RPM.
6) In intervals between 3 to 5 spoonful additions prepare a
0.2 mol. eq. of CuCl2·2H2O or 0.0874 mol or
14.9 g. This is a much much larger amount than the usual 0.1 mol eq. Why not use more? Dissolve in a minimum amount of 50% IPA. Or about
30 mL IPA + 30 mL dH2O. The copper chloride dissolves better in water than in IPA.
7) Addition of the nitrostyrene takes about
1 hour. Temperature does not rise above
18 ° C. There is foaming present, but large additions of ice, and overhead stirring work well to keep everything in check. The orange hairs disappear, left with a mostly white milky layer. Pour in an additional 50 mL IPA used for cleaning the sides of the flask.
8) Out of the 20 g additional NaBH4 add a total of 18 g and leave it to spin at room temp, for an additional 50 min having removed the cooling bathe.
9) Set the flask on a heating mantle.
10) Use a 20 mL pipette to draw up the CuCl2 and squirt deep into the vortex almost in the liquid layer. A long and large 50 mL or 100 mL glass pipette would be even better. The pipette works wonders, helps to reach deep into the vessel and you can totally control the reaction this way.
The reaction is still violent, lots of smoke is produced that wooshes out of the open neck. So wear a glove on the pipetting hand. Just make sure the reaction is energetic as can be without spilling over. The pipette lets you control everything and if you pipette out as close to the surface of the liquid as possible near the vortex, splashes are also reduced this way.
Maybe with two quick squeezes pour in the CuCl2. Nothing is spilled, the heating mantle is not destroyed. As well as there is a lot of flammable H2 produced at this point, make sure no sources of sparks or flames are in the vicinity of outlets.
11) Place a large condenser on one of the necks, a 600 mm Allihn with cold water flowing. Turn on the heat to maybe 140 C. The IPA really starts to boil, and the condenser can’t deal with all of it, but it helps a great deal. Most of the IPA condenses and falls back, it really boils at a quick rate initially. If done correctly not that much IPA boils off.
If going for a larger scale, a 200 g reaction, I would use 2 Allihn condensers of an equal size.
Stirring speed is increased at this point, to about 350 RPM, but watch the temperature closely, and make sure nothing boils over.
12) Once the initial thrashing and violent boiling settles down, temps have stabilized, reflux at a
max of 78 ° C for 45 min. About 3 drops/ second at reflux.
13) Remove from heat, you can stop stirring, and let the reaction
cool down a bit to about
50 ° C. Pour your reaction layer into a more convenient beaker and filter the copper floating on the bottom of the upper (IPA) layer. Filter twice over a large Büchner funnel with medium filter paper. A small amount of black copper particles remain, it is not a big deal.
14) Now pour the still warm reaction mixture into a 2 L sep. funnel. The bottom, water layer goes into one beaker, the top, IPA layer goes into another beaker. Have about 900 mL of the IPA layer which is cloudy. But most importantly the colour is only a light yellow. It is not golden, it is not brown it is not black. Cloudy with a light yellow. Looks very good.
15) Most of the goods are in the IPA but I go for max effort and with fresh IPA extract twice from the aqueous layer. 100 mL and 50 mL IPA. The aq. layer has a bunch of dissolved borates. But if we do all of the work in the sep. funnel and filter while everything is warm borates shouldn’t crash out.
16) Now have a combined amount of about
1100 mL of the IPA. Discard the aq. layer.
17) Wash + dry in a sep. funnel 2x with
K2CO3 brine. Wash volume is about 20% of the IPA layer. Combine 120 g K2CO3 with 110 mL dH2O for 220 mL of the brine.
18) Wash + dry with 15 g
MgSO4 but I believe this is too much layer was mostly dry. Still the layer after the MgSO4 was cloudy.
19) Gravity filter over medium speed filter paper folded into a flute directly into a 2 L one neck flask. Now the layer goes crystal clear, and has a light colour. (Shame I didn’t take a picture). Its pH is 11.2.
20) Distill off most of the IPA under vacuum. Do not have a good vac source so goes slowly. Distills at 36 – 38 ° C. Stop distillation as it is taking too long, have about 200 mL of the IPA layer left.
Now other options should be explored for getting the 2C-H. I have tried making the sulfate and that seems to work, but that was from a dirty IPA layer. So can not tell just how well. The acetate of 2C-H might precipitate directly from the IPA layer as well.
If one has a very good vacuum source you can dry distilling off the IPA, and then vacuum distilling off the amine.
21) I go for
HCl this time, the safe way, no oxalate fuckery. Calculate the HCl amount. If a starting amount of 0.437 mol. estimate for roughly 80% or 0.35 mol or
30 mL of 36% conc. HCl. Dilute this to 100 mL, but this is too much, can
dilute to 60 mL as well. Transfer the IPA to a pyrex plate.
22) Separate a portion of the IPA in case of over-acidification. Start pouring in the HCl and use all, actually use just a bit extra. Could indicate that the yield is more than 80%. Final
pH is 6.6.
23) Evaporate off the remaining IPA with mild heating, continue evaporating off the water until a thick paste is formed. Leave to fan dry.
24) Wash the dirty yellow - orange 2C-H HCl with cold ethyl acetate in a Büchner funnel mixing well, filter. The EtOAc seems to help carry off remaining water. Leave to fan dry. The yield of 2C-H HCl from the reaction mixture is
76.432 g. Mol. wt. of 2c-h HCl is 217.693 g so I have
0.351 mol or a yield of
80% from the nitrostyrene. A very very good initial yield of some fair looking 2C-H, but it still needs to be cleaned further.
25) Will preform an A/B extract. Basify with KOH (can use NaOH as well). Use a bit of a mol. extra so use 0.368 mol KOH or
20.68 g dissolved in
100 mL dH2O.
26) Mix the 2C-H with 700 mL dH20 in a 2 L beaker with magnetic stirring. It does not fully dissolve, but that is ok, when we basify it will dissolve. Add the hydroxide until a pH of 11.5. Now have 800 mL of the aq. Layer with the freebase floating around.
27) Pick up the 2C-H freebase with DCM in a 2 L sep. funnel. Extract 3 x using 150 mL, 100 mL, and 50 mL DCM.
28) Now I believe I made a mistake here and could have tried adding conc. HCl. directly to the DCM with strong mixing. Then attempt to pick that 2C-H HCl with water? Or at least tried. If I end up with not much 2C-H product, can just evaporate the DCM.
Another option might be to add GAA (AcOH) to make 2C-H acetate. That will form from the DCM directly.
The problem with the HCl is that it is aq. And that in theory doesn’t mix well with DCM.
29) Decide to evaporate off the DCM in a pyrex dish on a hotplate with mild heating (in a fume hood). When most of the DCM is gone the 2C-H freebase will start converting to the carbonate salt from contact with air. Not a problem.
30) Once again prepare
30 mL of conc. HCl that I dilute a bit to 50 mL. Leave a portion of the watery carbonate layer out in case of an overshoot. Add the HCl until a good pH (mid 6s).
31) Evaporate most of the water and clean with cold EtOAC, suck with a vacuum, also clean with acetone but that seems to carry off product away (just like with 2C-B). Makes for a whiter product however.
32) After the A/B extract I have a final
61.423 g 2C-H HCl, so a yield on the A/B of 80%, or 65% from the initial nitrostyrene. Could have been borates in the crude 2C-H, or maybe I still don’t know how to do a proper A/B or the acetone carried product away.
Final stuff looks pretty good. Not totally white but this crème colour. Fine powder with some chunks. Good enough to make 2C-C, 2C-I, or 2C-B.
Some key take-aways:
- Can use less than 13x of liquid, maybe even go less to 10x combined IPA + water (eg. try a reaction with 200 g nitrostyrene and 2000 mL combined IPA + water in a 10 L 3 neck flask.)
- Can use less than a 7.5 x eq of NaBH4
The large pipette helps so much in controlling the copper reaction, way safer than pouring directly into the neck.
- Effective cooling with 2x large Allihn condensers helps prevent loss of IPA (can use less liquid without borates crashing out).
- After addition of copper make sure to not heat your mantle too much. Keep temp. at or a bit below 78 ° C. If it heats up too much the whole IPA layer will darken and yields possibly reduced.
- Filter and separate layers while everything is still warm.
- Ideal scenario would be effectively vacuum distilling off the IPA then increasing heat and vacuum distilling the 2C-H freebase.
- Salting with HCl works well also no need for oxalate, just takes a bit more work.
Sorry but took no pictures this around. Key thing to look for is the colour of the IPA layer post reaction, if it is cloudy and a light yellow but not a dark yellow then it is good.
