sonogashira
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Amine alkylation help needed..
I would like to alkylate a primary amine dissolved in isopropanol so that i end up with the diethyl version of this amine (i.e a tertiary amine
overall)
I found a procedure that uses ethylbromide; i was wondering if ethyl iodide could be substituted for this, and if so what this would do to the
reaction (more vigourous?)
I've also seen that a base is needed, but almost all examples i've seen use hard to get tertiary amines.. Could an inorganic base be used? (sodium
hydroxide/carbonate etc.)
Thanks in advance
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Nicodem
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Ethyl iodide can be used instead of ethyl bromide. There will be no particular influence on the reaction except for it its faster proceeding.
You need to use the Hunig's base (EtN(i-Pr)2) as HX scavenger since it is the simplest amine which can not form quaternary amine salts, but can still
get protonated. Alternatively, you might try using K2CO3 (in no less than 1:1 mol ratio with EtI). Since K2CO3 has a very low solubility in alcohols,
you will need to use efficient stirring.
Na2CO3 would probably fail while hydroxides would compete with the amine as nucleophile thus consuming EtI. I can't think of any other base that might
work, except for K3PO4 which is however a bit too basic for such use.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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sonogashira
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Thanks for the quick response Nicodem.
Hunig's base is indeed the one i have seen used. I could buy it i suppose, but it would be good if i could find a replacement (even if that meant a
drop in the yield)
There was one thing that confused me.. why would potassium carbonate work whereas sodium carbonate wouldn't?.. It would be nice to use sodium
carbonate since i have that.
Anyway, K2CO3 and EtI seems worth a try. Many thanks 
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Eclectic
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Does anyone know of a synthesis for Hunig's base? (I've U.T.F.S.E)
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sonogashira
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(iPr)2NH plus EtBr?
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Eclectic
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Maybe. Here is the original article ref: Chem. Ber. 1958, 91, 380
Unfortunately, I don't have access to it. There are also some Japanese patents, but I can't read them. They seem to involve reductive alkylation.
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Nicodem
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| Quote: | Originally posted by sonogashira
There was one thing that confused me.. why would potassium carbonate work whereas sodium carbonate wouldn't?.. It would be nice to use sodium
carbonate since i have that. |
In my experience Na2CO3 nearly always fails as a base when used for alkylation of phenols (and when it works, the reaction takes much, much longer and
gives lower yields). No wander in literature it is never used for such purposes (except in aqueous media). It is way less soluble than K2CO3 in
organic solvents and also less basic (unlike in water where they are more or less equal) so I would guess one of such things might be the reason.
Still, Na2CO3 might work for amine alkylations since ammonium ions are somewhat more acidic than phenols, especially if used in solvents like
acetonitrile or DMF where it should be better soluble. However, given that K2CO3 is cheap and easy to obtain I would not even waste time trying.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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sonogashira
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Thanks Nicodem, you've been a great help as always 
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not_important
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| Quote: | Originally posted by Eclectic
Does anyone know of a synthesis for Hunig's base? (I've U.T.F.S.E) |
Given that it doesn't form quaternary salts, the first though is to react ethyl amine with isopropyl bromide or similar. But then I saw the attached
procedure for making di-ethyl isopropyl amine, and it appears some extra work is going to be needed to make the reaction go.
An alternative that doesn't require ethylamine to start with might be to pass ammonia and EtOH+iPrOH in a 1:2 ration through a hot tube containing
finely divided copper or nickel metal, then fractionate the condensed products. Di-isopropyl-ethyl amine boils at 127 C, di-ethyl-isopropyl amine at
108 C and appears to be much more soluble in water than Hung's base. So condense, wash with some but not excess amount of water, then fractionate for
the 127 C cut. Other likely products are triethyl amine bp 89 C, and less highly substituted amines which will be water soluble and of lower boiling
point.
Attachment: DiethylIsopropylAmine.pdf (58kB)
This file has been downloaded 730 times
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sonogashira
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Nicodem: "Since K2CO3 has a very low solubility in alcohols, you will need to use efficient stirring."
Any idea where i would be able to find such solubility data? Specifically K2CO3 and Na2CO3 in isopropanol.
In fact, if someone could shed some light as to how i would go about this process in general.. is there a book which lists such solubility properties
that someone can recommend?
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Nicodem
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What do you need the solubility data for? I thought you just want to ethylate your amine?
Just do it like it is normally done, except for using magnetic stirring since you will have lots of solid K2CO3 (<-must be anhydrous, do not use
the hydrate!). Set on reflux and follow the reaction with TLC (don't forget to add ~1% Et3N in the mobile phase!). The reaction will take considerably
more time as if when you would be using the Hunig's base.
PS: Avoid exposure to EtI. It is toxic and carcinogenic.
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sonogashira
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Since you were talking about the solubility of potassium and sodium carbonate in organic solvents I assumed that the base needed to be dissolved.. it
seems not!
I'm just curious as to where i can find such information anyway.. there must be a better way than searching on google.....
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497
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Sorry to bring up this fossilized thread, but my question is directly relevant.
Could you use methanol as the solvent instead of isopropanol? K2CO3 is pretty soluble in MeOH, so wouldn't this reduce the need for stirring and a
long reaction time?
Also Nicodem states above that the conditions must be anhydrous, what effects will a small amount of water have on the reaction? Would it just result
in side reaction of hydrolysis of the alkyl halide? Or is there a more problematic effect.
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Nicodem
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I said K2CO3 should be anhydrous (but forgot to mention that it should be powdered as well). If the solvent contains moisture then K2CO3 will get
hydrated and thus its solubility decreases. With MeOH or DMF as a solvents, this is not that much of a problem, but it is a problem particularly with
acetone or acetonitrile. Also, it is strange that you think water would be problematic because of consuming the alkyl halide via hydrolysis. If that
was the case, then using MeOH would be a source of the same problem as it is roughly just as nucleophilic as water. Instead most amines are way more
nucleophilic than water or alcohols and this is why these can be used as solvents in most cases. Obviously, since you did not describe the reaction
you are asking about, nobody can give you a reliable answer if using MeOH is a good idea or not.
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497
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| Quote: | | If the solvent contains moisture then K2CO3 will get hydrated and thus its solubility decreases. |
Ah I neglected to consider that problem.
| Quote: | | Also, it is strange that you think water would be problematic because of consuming the alkyl halide via hydrolysis |
I was just speculating about that.. But I'm glad to hear a little water won't cause too much harm to the reaction directly, other than its effects on
solubility of the reagents.
According to this K2CO3 is soluble to at least 1g/100g MeOH even in its hydrated form, so am I correct in assuming that the reaction would proceed even with
hydrated K2CO3? The only reason I ask is that I would like to avoid ordering anhydrous K2CO3, and I have no good way to dehydrate the stuff I can make
myself from KOH.. Unless anyone knows an easy way to do it without heating over 300*C?
Interestingly, according to this reference, even Na2CO3 is soluble to about 0.25g/100g MeOH, so maybe it would be a usable alternative?
The specific reaction I was contemplating was the alkylation of a primary amine with isopropyl bromide to form the corresponding diisopropyl
derivative. I can't think of any reason using MeOH as the solvent would hinder the reaction, but I wanted to be sure.
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Nicodem
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Quote: Originally posted by 497  | | The specific reaction I was contemplating was the alkylation of a primary amine with isopropyl bromide to form the corresponding diisopropyl
derivative. I can't think of any reason using MeOH as the solvent would hinder the reaction, but I wanted to be sure. |
As far as I know and as far the literature is concerned, amines can not be diisopropylated with isopropyl halides or sulfonates. I explained this
already more than once, so UTFSE. And while you are at it, check also the mechanism of the SN2 substitution to better understand why is such a
reaction unfavoured. If you have a reference that claims otherwise, show it to us, so that we can see what is it about.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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turd
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| Quote: Originally posted by Nicodem | | As far as I know and as far the literature is concerned, amines can not be diisopropylated with isopropyl halides or sulfonates. I explained this
already more than once, so UTFSE. And while you are at it, check also the mechanism of the SN2 substitution to better understand why is such a
reaction unfavoured. If you have a reference that claims otherwise, show it to us, so that we can see what is it about. |
?
I'm sure I'm missing something completely obvious, but:
http://www.erowid.org/library/books_online/tihkal/tihkal04.s... and http://www.erowid.org/library/books_online/tihkal/tihkal37.s...
| Quote: | | A solution of 1.60 g tryptamine base in 10 g melted sulfolane was treated with 8.5 g isopropyl iodide and 6.5 g diisopropylethyl amine, and held at
steam bath temperature for 12 h with occasional shaking to mix the two phases. This mixture was then added to 100 mL H2O, and extracted with three 30
mL portions of hexane. These were combined and, after removal of the solvent under vacuum, the residue was distilled at the KugelRohr to give an
off-white oil boiling at 170-185 °C at 0.05 mm/Hg weighing 1.37 g (56%) that spontaneously crystallized to a solid, mp 69-71 °C.
Recrystallization of a sample from hexane produced a white product with a mp of 72-74 °C. IR (in cm-1): 742, 791, 1009, 1133, 1162, 1198. MS (in
m/z): C7H16N+ 114 (100%); C4H10N+ 72 (38%); indolemethylene+ 130 (18%); parent ion 244 (<1%). A solution of 0.50 g of the free base in 2.5 mL
isopropanol was treated with 0.5 mL concentrated HCl and slowly diluted with Et2O with good stirring. There was thus obtained, after filtering,
washing and air drying, the hydrochloride salt with a mp of 192-193 °C. The infra-red spectrum of this salt was the same from either source; IR (in
cm-1): 752, 773, 935, 972, 1138, 1183. |
Also somewhat related:
Alkylation of aniline with isopropyl sulfate:
Organometallics, 17(19), 4202-4205; 1998
Reductive alkylation of aniline with acetone:
Magyar Kemikusok Lapja, 43(10), 361-5; 1988
Could the resulting N,N-diisopropylaniline be a replacement for Hünig's base? I fear not, since there are some quaternary ammonium salts with this
skeleton.
Edit: The reported mps for both DIPT procedures (from indole and from tryptamine) are quite different (198°C vs 192°C) - maybe Shulgin only got
mono-alkylated NIPT?
[Edited on 19-8-2010 by turd]
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Nicodem
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I must be getting old! How could have I forgoten that one?
So what I just did was to leave all my work, sit in front of Beilstein and check all over again. Found nothing. Not a single example of a
diisopropylation of an aliphatic amine with isopropyl pseudo(halides). Not even one example of any other "diisoalkylation" (alkylation with R2CH-X),
except for a few examples with 1,4- or 1,5-disulfonates (but here the second alkylation is intramolecular, thus facilitated and less susceptible to
steric hindrance). The only diisopropylations were those of anilines (all similar to the one in Organometalics paper above), but this is more
or less irrelevant as anilines are about 100000-times less basic than primary amines, so that E2 elimination is not a problem if no base is used like
it is described. So, with anilines, you can heat them up and wait for as much as you want. I did not check SciFinder because I already did so time ago
when replying in some other thread.
| Quote: | | Could the resulting N,N-diisopropylaniline be a replacement for Hünig's base? I fear not, since there are some quaternary ammonium salts with this
skeleton. |
No, anilines are weak bases. BTW, are you sure there exist alkyldiisopropylanilinium salts?
| Quote: | | The reported mps for both DIPT procedures (from indole and from tryptamine) are quite different (198°C vs 192°C) - maybe Shulgin only got
mono-alkylated NIPT? |
I don't think so. Beilstein gives 236-237°C for NIPT hydrochloride. Maybe Shulgin succeeded in doing something nobody else reported anywhere? To bad
TiHKAL is not abstracted by Beilstein and SciFinder. I would at least get one hit.
Sulfolane is the best there is for SN2 substitutions, but as far as I know, it is good only in the SN2 where the nucleophile is anionic (which is not
the case with amines). Time ago I was isopropylating an amine with a -CH2NHMe group and I only got a ~50% conversion after many hours of heating. I
used DIPEA in DMF and a huge excess of isopropyl bromide. And that was only an N-methyl primary amine, not a stericaly hindered N-isopropyl alkylamine
like the intermediate in diisopropylation! That left me with an impression that any isopropylation of amines is extremely inefficient. After that
experience I would go for a reductive amination of acetone any time.
A bit off topic edit: I went to answer my question about alkyldiisopropylanilinium salts to myself. Indeed there are such compounds according to SF.
These are mostly aniliniums that have the quaternary nitrogen as an endoocyclic part of the cycloaliphatic system (piperidine, pyrrolidine, etc.),
thus less crowded due to rotational restriction, but there actually are a few non-cyclic examples (which is something I find extraordinary). In the
aliphatic amine series there are only some compounds with the dialkyldiisopropylammonium moiety as part of the cyclic system (kind of acceptable), but
none with nitrogen not being part of cyclic systems. Anybody has an explanation on how can this be?
[Edited on 19/8/2010 by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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497
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Hmm... discouraging. I suppose I'll have to do some experiments and see what happens.. Does anyone have suggestions for an easy way to
differentiate/separate the monoisopropyl from the diisopropyl amine in the presence of an indolic nitrogen on the molecule? I've looked around online,
but haven't found anything that looked doable with basic reagents yet..
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chemrox
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@nicodem- I tried the K2CO3 trick last year trying to make N-alkyl piperidones. Despite grinding the K2CO3 "powder" as fine as I could in a small
ball mill, I still had very poor yields. I ended up making the target cmpds via condensations. I wonder if in the case of alcohol solvents a PTC
would help? Or could the K2CO3 be dissolved in water and then mixed into the alcohol? What is K2CO3 solubility in THF? could THF be used for this
process?
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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chemoleo
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Thread Split
18-9-2010 at 07:06 |
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