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IUU
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[*] posted on 17-5-2013 at 07:43
question on scaling up


Greetings, SM. Thank you to Polverone for this inspiring resource.

I have what is no doubt a trivially basic question regarding scaling up a procedure.

The procedure in question is N-methylation of an amino acid. The goal is to monomethylate the amino acid with a minimum of dimethylation. The procedure as written claims to achieve this via a 15-minute duration at the mmol scale.

My question is: when scaling this up to .1 mol scale, should this duration be expected to increase? And, if so, is there any rule of thumb for increasing this duration in proportion with the increased scale?

Thanks in advance for any insight.
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Hockeydemon
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[*] posted on 22-5-2013 at 00:08


Depends.. I don't know anything about monomethylation..
1mmol/ml is = 1Molar = 1mol/L
1mmol/g = 1 molal = 1mol/kg
As long as you keep the concentrations the same I see no reason for the duration to change.

Someone correct me if I'm wrong?
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woelen
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[*] posted on 22-5-2013 at 00:47


The answer to your question depends on the nature of the reaction. If it is strongly exothermic or endothermic, then you may need shorter resp. longer reaction times when the reaction is scaled up. If the reaction hardly leads to heating up or cooling down of the vessel, then I expect that scaling up does not need other reaction times (provided the mixing of the reagents is as well as in the smaller prep).



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IUU
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[*] posted on 9-6-2013 at 03:05


Thank you for your response, woelen.

The reaction in question is exothermic, but not "strongly" so (at least by my admittedly novice judgement). The heat generated brings the vessel to ~ 27 C over the course of about ten minutes (starting from room temperature).

I'm not sure what you mean by "shorter resp. longer" in your post. I'd appreciate it if you could elaborate on that point.

Regarding the mixing of the reagents, constant vigorous manual stirring throughout the fifteen minutes of the reaction means that, as far as I can tell, the mixing of reagents is as thorough as it can possibly be.
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Bikemaster
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[*] posted on 9-6-2013 at 06:25


If you don't change the temperature at which the reaction is taking place and you keep the same concentration that they did, the reaction time will be indentical to their results. On the other hand, this is only true if your heat transfert and your mass transfert stay the same. To acheive this, you need good mixing and good heat transfert.
I don't know how big your scale up will be, so it is hard to know if you need cooling or not. But you have to remember one thing, a bigger vessel offer less exchange suface by volume of reaction that a small one, so your heat transfert will go down and the temperature of your mixture will go up, giving your a faster reaction rate, but maybe some decomposition. Also, the reactions don't respond lineary to the increase of temperature, so be sure to never past the "runaway point".
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DJF90
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[*] posted on 10-6-2013 at 10:25


You havent said what your initial scale or reaction is, but you do say you're scaling to 100 mmol. This isn't an awefully large amount, and many people here do reactions for the first time on this sort of scale. Now while you can say it'll take just as long with the same relative proportions of reactants and stuff, and this might be the case, but you should really IPC the reaction (thats an in-process check for those not in the know; TLC at a minimum, but if you have access to other instrumentation (HPLC, LCMS, NMR) they may be more applicable (some reactions CAN'T be followed by TLC)) to confirm the progress of the reaction. That'll allow you to increase reaction time or charge more reagent if necessary. If you've overshot the reaction coordinate you desire, you'll have to re-start with fresh reagents and alter the reaction conditions or reaction time to compensate.

This applies to all reactions, whether first run through, or a scale up of a previously successful reaction. If the scale up is more than 10x the previous scale, you should ideally re-evaluate the hazards involved (you've heard of a COSHH assessment, right..?). You haven't said if you've run the reaction before or not, but you say you've got a procedure on mmol scale. If you're running through this for the first time, try working with a gram or 5mmol or something like that. If you're a competent chemist with a fair bit of experience (you're not or you wouldn't be asking...) then maybe a slightly larger scale is do-able (5-20g), particularly if the reaction is similar to something else you've done before.

Now, to your specific reaction. Can the transformation not be performed under alternative conditions that give selective mono-methylation? The sequence primary amine => benzaldehyde imine => N-methyl benzaldehyde imine => N-methyl amine has been described at OrgSyn. If the alkyl group you're wishing to introduce has a readily available aldehyde, then a reductive alkylation might be your best bet (I've done this to make N-benzyl anilines before). I've also made an N-methyl aniline by in-situ borane reduction of the N-phenyl formamide, using NaBH4/BF3-Et2O. Both gave fairly good yields. (ca. 70 % and 90 % respectively).

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IUU
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[*] posted on 10-6-2013 at 13:29


Thank you for taking the time to write such a detailed response, DJF90.

I appreciate the utility of TLC; I should put together a TLC setup (no access to other instrumentation: I'm strictly an amateur, and my current equipment is limited to the bare minimum (DIY hood, respirator, etc. included)).

Regarding hazards: the only reagent in this reaction that is at all hazardous is formaldehyde, and in my scaled-up procedure only 27 ml (of 37% aqueous solution) is used.

I accept your rebuke as to my lack of competency and experience: I have only a rudimentary chemistry education, besides a patchwork of the always-dubious self-taught knowledge.

I've run two scaled-up variations (one 50 mmol, one 100 mmol), but have not yet had the opportunity to test their products due to recent lack of time for this hobby (work, etc.). (Solubility test is useless in this case AFAICT, so melting-point is my recourse, and the target compound's melting-point is in excess of 300 C, so a new thermometer must be acquired prior to the test.)

Alternative conditions: I am aware of the borohydride route, but the cost of NaBH4 is not enticing. Thus, I decided to try the current route instead.

Specifics: I apologize for the vagueness in my post, but it is purposeful. The reason for it is that the reaction in question, based on other topics here wherein it was mentioned, seems to attract precisely the kind of kewl blather that is this site's bĂȘte noire. In light of this, in an attempt to avoid deteriorating the discourse here, I've forborne from mentioning the specifics that would likely trigger such. The original procedure is in Tet. Lett. 48 (2007) 7680-7682 (da Silva, et al.)
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Hockeydemon
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[*] posted on 11-6-2013 at 05:47


If you think that the people on here will consider what you're attempting as 'kewl', and you have admitted to a rudimentary knowledge of chemistry with a limited amount of equipment don't you think you might be doing something inadvisable? The people on here are pretty accommodating to the science of most anything as long as it isn't for illicit drug/bomb synthesis.


Here is the file you referenced in case anyone wanted to see it:
http://www.versuchschemie.de/upload/files2/96730940_2807.pdf
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IUU
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[*] posted on 11-6-2013 at 11:13


Hockeydemon,

1. I have adequate equipment for this procedure, thoroughly grokked the hazards of formaldehyde, and used safety equipment with Zubrick as my guideline.

2. I was under the impression that "kewlness" had to do with lackluster quality of discourse and blithely posting non-referenced crap outside the Beginnings section (where we are, incidentally.....) I'd say "correct me if I'm wrong", but you're not an administrator, just apparently an aspiring self-appointed hall-monitor, and given your earlier *contribution* to this thread ("I don't know anything about monomethylation..") it's not clear why I or anyone else would give a fraction of a damn about your opinion. You'll note that I didn't respond to your earlier post: ergo, I wasn't talking to you, champ. If Polverone, Nicodem, or another administrator expresses anything similar about my posts, then I'll take notice. Elsewise, get stuffed.

3. You speak for the "people on here" as a class? Is this an elected position? Pfft.

4. The product of this reaction is not illicit, nor is it explosive.
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Hockeydemon
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[*] posted on 11-6-2013 at 16:00



You're quite a few negative adjectives hahaha. I'll start by defining 'k3wl' for you..
Quote:

K3wls are people, most commonly troubled teenagers, who feel unaccepted by the society and thus constantly call for other k3wls' attention and general pity by pretending illiteracy, criminal intent, self-destructiveness, general irresponsibility and idiocy. The lack of tolerance toward such people is due to their unsurpassed ability to cause a rapid degradation of any forum.


I'm actually pretty surprised how quickly you turned into a complete dickhead for absolutely no reason. You used a word incorrectly that implied the exact opposite of what you're defending. Then proceeded to personally attack me for asking about it. I couldn't be less of a 'hall monitor' - I really don't care what other people do.

The world isn't out to get you kid.. I attempted to answer your question (I was more or less correct too), and then was curious about what you were doing because of your intentional vagueness. You could be making meth for all I care - the mods on the site do a good job all on their own.

I was also implying that the people on this site are very open to the science of most things. I don't even know how you turned that into a negative statement.
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elementcollector1
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[*] posted on 11-6-2013 at 16:22


I'm beginning to see a pattern with the new members on this board: Ask a question, get a few good responses, get a criticism, OP violently 'defends themself', thread turns into a flame war. Can we just not do that?
Hockeydemon: If he (assuming, IUU, that you are in fact male) referred to this synthesis as attracting k3wls, and stated that he had a rudimentary knowledge of chemistry, he already has self-doubt. Instead of criticizing that without base, give him some knowledge: Is there anything he's looking over? Forgotten / never knew in the first place? Post it.

IUU: No one's calling you a k3wl. I'm always glad to hear another person has found an interest in home chemistry. To answer your question, I think DJF90 is right: 100mmol shouldn't pose any sort of a hazard in terms of heat. I don't know if it will affect purity of your product (decomposition by heat? Maybe?), as I have no clue what your product is.




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Organikum
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[*] posted on 11-6-2013 at 16:33


And thats enough. Ok?


IUD, I suggest you use a vessel at least twice the size you would estimate as "normal" and most important a condensor deserving this name (anything yoou can look straight through does not) with - most important, rarely told - a wide bore and connection to the flask.
As when things get really going it is not the size of the flask which never really suffices in such situations, but the size of the bore which causes trouble.
When the angry things try to squeeze through a tight openeing this works as a nozzle and causes an astonishing acceleration. Next stop is the ceiling and then back on your head.
I know what I am speaking of, trust me on this.... :cool:

And loosen up a bit, no need to be so stilted. But please when you name a reference provide a link to download or attach it. Otherwise is pretty nervy and unpolite.

Hey Hockeydemon! Your first response was rather ambiguous to put it politely and for somebody insecure easily to misunderstand. Pls try to see the situation of the addressed one, will ya?
Ten years and some thousand posts later you get grumpy and offending. Like me. But then thats regarded as personal style.... ;)

PEACE !
/ORG
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watson.fawkes
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[*] posted on 11-6-2013 at 17:25


Quote: Originally posted by IUU  
Specifics: I apologize for the vagueness in my post, but it is purposeful. The reason for it is that the reaction in question, based on other topics here wherein it was mentioned, seems to attract precisely the kind of kewl blather that is this site's bĂȘte noire. In light of this, in an attempt to avoid deteriorating the discourse here, I've forborne from mentioning the specifics that would likely trigger such. The original procedure is in Tet. Lett. 48 (2007) 7680-7682 (da Silva, et al.)
This paper has been discussed on this forum before; see this post. Its title is Reductive methylation of primary and secondary amines and amino acids by aqueous formaldehyde and zinc. There are 26 substrates listed in Table 1 of that paper. There are two entries in this table that are amino acids with 15 minute monomethylation times: alanine and isoleucine. Of course, another reference to this paper is in this post on the shake and bake method, in particular, the synthesis of pseudoephedrine via n-methylalanine.

Whatever label you might deserve, "k3wl" certainly isn't the right one.

Moral: If you don't want to be investigated, don't be evasive.
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Hockeydemon
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[*] posted on 12-6-2013 at 00:55


Watson.Fawkes you made my day.


To everyone else.. Yes I could have stated things in a more polite way to the OP, but I did not see my post as overly rude in the first place. Obviously he thought different..

Next time.

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[*] posted on 12-6-2013 at 13:00


Quote: Originally posted by Hockeydemon  
Watson.Fawkes you made my day.
Thank you.

I should add one other thing, the general principle that I'm operating under that set me off. Behaving in a scientific manner is incompatible with evasion and furtiveness. The rule on this forum, a sensible one, is that you can discuss (mostly) whatever you like if you do so in a scientific manner. The most common failures are in lax terminology and notation, ignoring the lab notebook, lazy thinking, etc. Yet I consider saying that "I have a problem, but I'm not going to disclose all the details" just as unscientific.

Science is a joint activity, not an isolated one. The principle of reproducibility in scientific results presumes an openness that everything necessary has been disclosed, that nothing important has been kept secret. This principle is not always adhered to, but the principle remains. As a result, I feel perfectly comfortable saying here that IUU's has not been discussing his problem in a scientific manner.

In this case, it's also ludicrous. Scale-up behavior depends on the ΔG of the reaction and on the thermal conductivity of the reaction mixture. How would anybody even begin to know what the scaling behavior is if you don't know the reaction?

Also, this reaction has also appeared in the following thread, whose non-evasive title is N-Methyl-d,l Alanine.
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