Okay, here we go. If I may, letters (and anyone else who can chime in) I'd like to ask some questions and clarify some things, line-by-line. That could be the easiest way here.

take 74.27g of methylamine.hcl (1.1mol), dissolve in the minimum amount of water and write it down.
add toluene (5-10 times the amount of water) then drop in 1mol of NaOH flakes (40g), slowly while in an ice bath.

I'm going to eliminate the ambiguous spread here, and just say 10x the amount of water, is that okay? And this could use stirring, right? You mention shaking, but not stirring (shades of James Bond). I'd like to do this all with clamped, set-up glass if possible.

And the ice bath mentioned, that can be set up in advance, correct? In other words, that first step of dissolving the amine in water can be done in glass that's already in said ice bath, right?

then add more NaOH, 6-8g per every ml of water present. So if you had to dissolve your amine in 50ml water, you must add 300-400g dry NaOH.

Again, the "6-8" is ambiguous to me as a layman; I have no idea why to choose one end of that spectrum over the other. Can we just go w/the maximum, and say 8g per mL?

Then add 150g more NaOH to account for the water formed by the reaction between OH(-) and MeNH3(+). Shake well and let sit in the ice bath till everything settles down.

Please describe what it was doing that it now has to "settle down." Exothermic action? Mild bubbling? Heavy frothing? I will need to know in advance. I'm also wondering again about stirring vs shaking. If this is a fixed glass setup, I'd rather be stirring, but maybe this is too much solids to be magnetically stirred...? Maybe it *has* to be swirled by hand? Those are the kinds of physical details I need to get a grip on. (Those ratios look to me like there's enough liquids that it could all be magnetically stirred, but I'm not sure)

If there isn't even any need for a condenser or addition funnel, I guess we aren't talking about any kind of clamped glass setup, just a flask on a stirplate, right? If it's going to be mag-stirred at any point, I can't pick it up and shake/swirl it because there will be a stirbar in there (unless I pull it out, of course). These kinds of aspects are obvious to the seasoned pro, but for someone like me, every little detail of this type has to be known in advance. And are we sure there's no need for a more anhydrous setup, like having all the flask necks stoppered except for one, with a drying agent plug in it?

Decant or filter your toluene, add to it some methanol and 0.9mol of your ketone, stir 30 minutes, then add 10~17g NaBH4 (depending on quality of NaBH4) in small portions in the ice bath, let stir extra 2 hours @ r.t. after addition of NaBH4 is done, and workup as usual. This works and is easy!

It's actually the whole reaction mixture that I'm decanting or filtering at this point, right? You say "decant the toluene" but I assume you really mean the entire mix since it is all intimate at this point. And what am I decanting away from---undissolved NaOH?

"Some" methanol is too vague, I'm afraid. Please give an amount, or an objective I can relate to (i.e. is the point to add enough MeOH to make the mix more easily stirrable?)

It will definitely be the greater amount of NaBH4 in my case because it is old NaBH4. I take it that it's added straight (dry), in small portions due to reactivity? It does visibly react, correct ? Maybe you could suggest something more specific as a way to add it (example "add portions of NaBH4 at a rate of roughly 0.5 g every 15 seconds until 17g has been added" or something like that). In the end though it will be more than 17g because we're going to scale this up to 100g ketone if we can.

If you will be kind enough to answer these questions (and help me adjust scale/amounts/moles to 100g ketone) I will then have more than enough to write up a very nice method!

Hi Methylman. Im feeling quite nice today so here goes :
First of all have a look at the mechanism for imine formation. It is attached.
As you can see this reaction is acid catalyzed (requires protons, yet the number of protons used is equal to number of protons released). At first the carbonyl oxygen gets protonated (attracts a hydrogen) to generate the carbocation as detailed in the picture. This carbocation reacts with the lone pair of the amine to create the second intermediate. one of the hydrogens bonded to the amine donates its bonding electrons to the charged nitrogen (to "neutralize" it) and is released in the form of a proton (so far we've have 1 proton in, 1 proton out). then the oxygen's lone pair again attacks a proton to generate a charged H2O group (charged water species), which is a very good leaving group (since water is quite stable). This ion leaves the molecule, along with the bonding electrons giving off water as a byproduct. Again a carbocation is formed, "steals" the lone pair of the nitrogen to compensate for the charge and a double bond is created. Then another hydrogen bonded to the nitrogen leaves, leaving the bonding electrons to neutralize the charge formed on the nitrogen, giving you an Imine as a product! Plz note - Some of the arrows in the reaction scheme are double arrows pointing to product and starting material indicating some steps are reversible and are in the state of equilibrium. Im too tired to fix the image now, but the main thing to remember is that the water releasing step is an equilibrium step, meaning the more water you have in your reaction vessel, the slower the reaction will proceed (this is called Le Chatelier's principle, look it up, its in wikipedia iirc). This is the main reason most aq. reductive aminations wont proceed well.
Also please note, all the curved arrows indicate either atom or electron transfer. the dots around the N and O atoms are lone pairs of electrons which are reactive in most cases. When you see an arrowed mechanism, always look at where the arrow is starting (should be either a bond, or lone pair or atom - when specified as "leaving").

Once the imine is formed, sodium borohydride is added and donates most likely a species called a Hydride, which can be thought of as an H(-) ion. The general mechanism for hydride donation is believed to proceed via a planar complex formed between the boron atom and the reducible species. Then hydride transfer proceeds in 90degrees compared to the boron location. This is non proven, but widely acceptable.

Whats important here is the imine formation mechanism.

take 74.27g of methylamine.hcl (1.1mol), dissolve in the minimum amount of water and write it down.
add toluene (5-10 times the amount of water) then drop in 1mol of NaOH flakes (40g), slowly while in an ice bath.

I'm going to eliminate the ambiguous spread here, and just say 10x the amount of water, is that okay? And this could use stirring, right? You mention shaking, but not stirring (shades of James Bond). I'd like to do this all with clamped, set-up glass if possible.

yes x10 the amount of water is ok.  Stirring is good, but when dealing with large amounts of solids, mag stirring is usually not good enough and mechanical stirring is required (i.e. over head stirrer). shaking is simply because its easier and faster then setting up and dismantling the overhead stirrer

And the ice bath mentioned, that can be set up in advance, correct? In other words, that first step of dissolving the amine in water can be done in glass that's already in said ice bath, right?

this *should* be set up in advance. however sometimes heat is needed to get the amine in solution. it is best to set up an ice bath on the side, make your solution in a minimum amount of water then chill it in the ice bath. this is due to the fact that dissolution can be endothermic (depends on your salt)!.

then add more NaOH, 6-8g per every ml of water present. So if you had to dissolve your amine in 50ml water, you must add 300-400g dry NaOH.

Again, the "6-8" is ambiguous to me as a layman; I have no idea why to choose one end of that spectrum over the other. Can we just go w/the maximum, and say 8g per mL?

8g/ml is good! it really depends on the purity and dryness of your sodium hydroxide, but to be on the safe side more is better here!

Then add 150g more NaOH to account for the water formed by the reaction between OH(-) and MeNH3(+). Shake well and let sit in the ice bath till everything settles down.

Please describe what it was doing that it now has to "settle down." Exothermic action? Mild bubbling? Heavy frothing? I will need to know in advance. I'm also wondering again about stirring vs shaking. If this is a fixed glass setup, I'd rather be stirring, but maybe this is too much solids to be magnetically stirred...? Maybe it *has* to be swirled by hand? Those are the kinds of physical details I need to get a grip on. (Those ratios look to me like there's enough liquids that it could all be magnetically stirred, but I'm not sure)

I say settle, as in let all the solids which are suspended in the mixture to settle to the bottom. when you later pour your toluene/amine solution, youd want it to be absolutely base free (as this can cause to self condensation of the ketone, accompanied by usually a red color).

If there isn't even any need for a condenser or addition funnel, I guess we aren't talking about any kind of clamped glass setup, just a flask on a stirplate, right? If it's going to be mag-stirred at any point, I can't pick it up and shake/swirl it because there will be a stirbar in there (unless I pull it out, of course). These kinds of aspects are obvious to the seasoned pro, but for someone like me, every little detail of this type has to be known in advance. And are we sure there's no need for a more anhydrous setup, like having all the flask necks stoppered except for one, with a drying agent plug in it?

as written above, hand shaking of the mix is good enough. however, you should always clamp your flasks, no matter what you do with them.

Decant or filter your toluene, add to it some methanol and 0.9mol of your ketone, stir 30 minutes, then add 10~17g NaBH4 (depending on quality of NaBH4) in small portions in the ice bath, let stir extra 2 hours @ r.t. after addition of NaBH4 is done, and workup as usual. This works and is easy!

It's actually the whole reaction mixture that I'm decanting or filtering at this point, right? You say "decant the toluene" but I assume you really mean the entire mix since it is all intimate at this point. And what am I decanting away from---undissolved NaOH?

you should decant only the upper toluene phase! if any water (containing dissolved base) is carried over or solid base you WILL get self condensation of the ketone. so in essence, you should only decant the top clear layer toluene/amine. for an added measure, if you dont feel comfortable enough with plain decantation, just run it through a flutted filter paper in a funnel. remember, up until now, all we are doing is just creating a dry solution of the amine in the toluene.

"Some" methanol is too vague, I'm afraid. Please give an amount, or an objective I can relate to (i.e. is the point to add enough MeOH to make the mix more easily stirrable?)

There are a few points in adding methanol :
1. the reaction solvent needed for the imine formation should be of the polar (preferably protic) kind. This is in order to stabilize the charged intermediates formed during reaction.
2. to make sure that when you add your NaBH4 it will dissolve and be able to react with the imine present in solution. Without the methanol, the borohydride would most likely just stay out of solution, out of phase, and will not react. You can think of it as a phase transfer agent of sorts, transferring the BH4(-) ion and its relatives (BH3(-2), BH2(-3), etc..) into the reaction phase.
If I had to recommend a specific amount, id go with a volume that equals 5 times the weight of the ketone. I usually add it by "feeling". Experimentation is your friend. try it with various amounts seeing which amount reacts the fastest and yields best for you.

It will definitely be the greater amount of NaBH4 in my case because it is old NaBH4. I take it that it's added straight (dry), in small portions due to reactivity? It does visibly react, correct ? Maybe you could suggest something more specific as a way to add it (example "add portions of NaBH4 at a rate of roughly 0.5 g every 15 seconds until 17g has been added" or something like that). In the end though it will be more than 17g because we're going to scale this up to 100g ketone if we can.

It is added dry, in small portions. Visual reaction does take place - some frothing. Whatever color formed in the imine formation step gradually disappears to give a white/yellow opaque mix. very good stirring is needed here. If you have an overhead stirrer, this is a must for good yields in the larger batches.
A better way to judge the amount of portions and addition time is to follow the temperature. you should add your borohydride at a rate which is slow enough to keep the temp below 10degC. so start by adding say 0.5g once, watching the temp. it will rise on addition of the borohydride and will drop back when most of it has reacted or has gone into solution. adjust your amount till you hit the sweet spot - the rate at which the temp stay low, but it doesnt take you all day to add your borohydride.

If you will be kind enough to answer these questions (and help me adjust scale/amounts/moles to 100g ketone) I will then have more than enough to write up a very nice method!

100g mdp2p = ~562mmol.
so for that i would use ~674mmol methylamine.hcl (~45.5g), and 10.4 of NaBH4, added in small portions.

a very important note - START SMALL , do a few 5-10g batches. Get comfortable with the reaction and the borohydride. Write down notes about color formation, disappearance, temps, times etc... There are many variables and things you might do that will fuck it up the first time you try it, especially the decantation from the base. doing 100g batch of a reaction for the first time is bad, especially on a precious ketone like mdp2p.

Hope this helps. Dont hesitate to ask more questions!

Thanks letters, wow that is some really great stuff. Your follow-ups were very illuminating. You definitely were feeling nice. Everything is getting clearer.

Okay I'm with you now on the decanting... now that you've elaborated, I see this part can just be done with a sep funnel, right? I was focusing so hard on other aspects that I forgot we were talking about mixing toluene and water (even though a small amount of water)... so, a separation in a sep funnel should be great here. I'm meticulous with the ol' sep funnel.

On the undefined portion of methanol--thanks, I will start off with your 5X ketone weight recommendation. Question though--this MeOH should be dry, no? And does it help if the toluene is dry, or is that pointless because it goes right on top of some water at that stage of things?

I hear you about not starting at 100g scale. That's probably a little overconfident... yet, I was under the impression that this thing doesn't throw nearly as many curves as the nitro Al-Hg. But 10g... ooh man that's tiny. If I get all my ducks in a row before I jump, I feel like I should nail it the first time. Maybe not with a killer yield, but at least a successful reduction. Tell ya what, I could start at about 50g ketone, that's a good compromise.  If the physical parameters you're describing are pretty accurate, I don't think I'll fuck it up. I more or less nailed the nitro Al-Hg my first time out by following the description in TS2, so I feel I should be able to handle this one, unless its subtleties are myriad and hard to spot.

It comes down to using our eyes. If I know what visible changes I'm looking for, I know whether things are working. If you remember any more visual cues you can advise me to look for, I'd love to note them.

Oh one last question please. Your description stops at the stage where I would need to add HCl to the reaction to destroy the boro. This task looks straightforward enough that I could lift the parameters for it straight from the "Wet NaBH4 reductive alkylation" text or any other NaBH4 reduction text that's out there. Agree?

cheers
MM

Thanks for the once-again fabulous follow ups, letters. 

Actually it's quite possible that by the time I get into the actual doing, I will have the hands-on help of a buddy who, very luckily for me, is a PhD biochemist. He doesn't know the NaBH4 reduction, he's only done some performic route work many years ago, but he certainly knows TLC (I don't yet) and would be able to help out with that part once he knows the overview of the reaction (he will end up reading all this material with me to prepare). So I'll be in good hands at that point... I mean ironically, I'll know more about this particular reaction than he will, but he will know all kinds of supporting stuff that will help a lot (TLC is a great example).

cheers
MM

Imine. http://127.0.0.1/talk/index.php/topic,1891.msg19862.html#msg19862

Yes indeed. I'll be back soon with a draft of the method incorporating all of letters' details. Fun stuff.

Great work methyl man you succeed. After doing the reaction several times you'll start to notice and experiment just because you're that familiar with it.

Go for it.

Thanks guys.

RR, thanks for that. Duly noted. We'll see whether Mr. Letters concurs, I'm giving him the first stab at all the amounts since his experience is what really drove this thing.

Hey methylman do a microwave reduction with your NABH4

look it up online there are some good refs on it  

consider the source, a forensic chemist.
no it does'nt have to be bone dry but i don't think that would work.
just bubble it in.