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solo
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problems with NaBH4 ....
Recently been experimenting with both the reductive amination of imines and the reductive amination of L-Pac using NaBH4. It all seems to go as
instructed in the journals except when doing the burn test a gummy substance shows up both in the ephedrine and the amine Hcl salt. Swim's question is
how important is the making sure the L-PAC and toluene are well basic before adding the NaBH4 ...will the lack of doing that cause the gummy substance
that won't go away after washings with chloroform, acetone, and ethylacetate. Will repeat the procedure again follow Barium's "a really wet
alkylation" for the reductive amination of L-PAC and will also check the PH of the imine prior to adding the NaBH4 for the imine reduction to see if
the amine Hcl salt is free of the gummy substance in the burn test after .
So, the purpose of all the narrative is to inquire if anyone has had similar problems and might have a solution that might be suggested to try....I
thank you....solo
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Klute
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Klute has incountered very similar problems using Barium's wet reduction methods, 2 phase aq./toluene, aswell as alcoholic homogenus (IPA, MeOH)...
very low yields <10%, and when non polar was extracted after workup, yield a gummy brown paste, who finaaly dried after a few days into a
crysatllin light brown mass. Washings with cold dry acetone, ethylformate, ether, etc provided only minimal cleaning... On the other hand, when the
amine base was directly crystallized by gassing the non polar, a cleanner product was obtained, whic still needed subsquent acetone washings and
recrystallization... Alot of alcohol was produced (maybe 30-60% depending on material and reaction), aswell as some strange purple to pink crystals
that crashed out from aqueuse or NP depending on recations... Some kind of salts from the hydride degradation? Inorganic, that's for sure. Ketones
used were of high purity, steam distilled, fractionnated, somethime coupled with a bisulfite complex/washing/release.... Alcohols and toluene were lab
grade or analytical +99.8% solvents, aswell as hydride....
He's guess was that the wet methods worked only with certain type of sub.ketones, the major problem being imine formation IHHO... even with >3x
molar excess of primary amine.
Anhydrous methods are yet to be tried.
Having pH>9-10 is the best way to avoid borohydride degradation... When making a basic solution of hydride, a important step is to dissolve the
tiny amount of NaOH in the dH2O before adding the hydride... Adding water to solid NaBH4/NaOH causes alot of fizzing before the base can dissolve
correctly, and thus degrades the hydride...
Those are his modest conculsion from his dogs experience...
A few other people claimed only bad yields or total failure with Barium's wet reductions, the substrate used must have a large influence on the
succes -or lack of it!
Good luck, and please share any improvements of any kind you could have heard of.....
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solo
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It's possible that unreacted imine may be in the mix and needs to be separated using column chromatgraphy with ethylacetate:toluene 8:2 as the eluent
with silica 60-120 as read in the ......
Biotransformation of benzaldehyde to L-phenylacetylcarbinol (L-PAC) by and conversion to ephedrine by microwave radiation
Vilas B Shukla,1 Virendra R Madyar,2 Bhushan M Khadilkar2 and
Pushpa R Kulkarni1
........that procedure was of course using microwave but the chemistry is the same and the problem was resolved .......similarly with catalytic
hydrogenation using Pd the same problem shows up ...hence Pt has been indicated in the literature as the catalyst to use....will do that and also the
column separation to find the cure......solo
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solo
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Actually Pd /C is fine ...however as the carbon chain gets longer than 5 the recomendation is Pt or Adam's catalyst. As for the fluid like material
that engulfs the final amine which keeps it from recrystallizing in it's salt form after heating ......only a liquid puddle with an amber color
results, upon closer look with a x100 microscope magnification I notices some amber strands and in the smaller puddles grains .......somehow it
reminds me of amorphous crystals or even yeast cells and strands...which perhaps means the L-Pac was not cleaned well and perhaps a trial cleaning
with an ionic resin, used with fermentaion products, to filter out any renmants or impurities........or I'm just drowning and throwing out some
possible solutions....or ...........solo
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chemrox
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similar issues
I'm doing a double red am using Na(OAc)3BH twice; once for a two-step with an aldehyde, reducing the immine after formation and the second with a
ketone moiety using aniline. I've been purifying reagents one by one .. distilled the aniline just prior to addition. This seemed trivial since it
all boiled at 184-5 and only the boiling chips showed any color.
The aldehyde is newly purchased reagent grade. I have an acid chloride I made that might have a higher boiling impurity .. I will distill it prior to
next use.. however I'm suspecting workup issues as my procedure was short on specifics. I suggested gassing the organic layer instead of shaking it
with 2N HCl as per published process and was told not to bother but I may try that.
There's another route I can try that would use NaBH4 .. the other intermediate made with a different approach. Problem is the first intermediate also
formed this gummy shit on stripping the solvent and I first suspected too much heat. Now I'm considering column chromatography as one of the starting
reagents is notorious for polymerizing and I haven't succeded in making the intermediate quanitatively as advertized. I might run this process
another 12-24 hours too. My solvent pairs are still a little less effective than ideal for the TLC monitoring.
I don't know where to start on the solvent system for the column work except to use the solvent I made the stuff in ... any recommendations in a
general sense ...
Solo, would you please paste me the part on the chromatography you were discussing? My product appears in the organic layer in which it is
compleletly soluble. Published procedure calls for dilution with DCM, a base wash, a water wash and an acidification with HCl. No details on these
given. Any advice on the specifics, assuming a pre-dilution volume of about 500 mls would be appreciated. Answers to Solo's dilemma are actively
sought as these will probably help with mine too.
[Edited on 3-4-2007 by chemrox]
[Edited on 3-4-2007 by chemrox]
[Edited on 3-4-2007 by chemrox]
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solo
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It appears that this is an old issue......
https://sciencemadness.org/talk/viewthread.php?tid=1938&...
I searched the archives but specific terms were needed to find this reference thread....solo
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chemrox
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strange sequence of items in the thread..seesm like there was a patent describing a catalyst for use in MW process but the patent turned out be
conventional hydrogentation technique to make methA but a catalyst was used to highten the yield. A bomb and H2 were still used but its likely this
could have been adapted to MW with formic acid or formate as the H source and it seems I've read this elsewhere. Thing is, I see no help here for the
current problem of Solo or me. Ours are different issues too, the common thread is that a reductive amination involving an immine intermediate state
is involved. I'm trying to do this without instruments and finding that a handicap. I don't know what Solo has in his lab. I just finished up with
the reaction sequence and have everything stirring in the pot under Ar for the night since I felt too tired to tackle the workup.
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solo
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Reference Information
A SUMMARY OF THE REACTIONS OF ALDEHYDES WITH AMINES
MURRAY M. SPRUNG
Chemical Review , 26, 297,(1940)
http://www.4shared.com/file/13535871/ba5e74ce/A_Summary_of_t...
THE CHEMISTRY OF IMINES
ROBERT W. LAYER
Chemical Reviews vol.63, isue 5, pg.489, 1963
http://www.4shared.com/file/11447263/4367762/the_chemistry_o...
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Klute
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Thanks for these Solo!
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solo
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I come to the conclusion that L-PAC will not be able to do any reductive amination or alkylation until the materialis removed from the toluene. Now
I've been told that the material with razemice with change in temp and its Ph, however I haven't read any of the material since most of it recommended
to me has been in the German language, hablo Español y Ingles pero no Aleman...., and I can´t claim knowledge of the language save my Spanish and
English.
I would gather one can use steam distillation to separate it from the non 'polar toluene, .......all in the name of keeping the material from
isomerization. Hence no spoon feeding here just suggestions on how to proceed, someone suggested AlHg reduction is the way to go, as mentioned the
L-PAC will not produce the amino alcohol without a gummy puddle residue.......both with the NaBH4 and with catalytic hydrogenation using Pd so I'm
assuming the toluene is the culprit......solo
Edit: I was just reminded that l-pac is not a ketone but an phenylacetylcarbinol..... an acylated alcohol.....but wait. I read something on March's
book on that ....time to review......
[Edited on 24-4-2007 by solo]
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solo
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I have finished trying the "wet NaBH4 reductive amination of ..." both the improved and the initial one with the same dismal results ....in the one
nasty smelling oil that nothing could be crystallized and on the other after removing the toluene......an amber trace of oil......since I worked with
5ml. samples it would seem something better than this would be the result.....will now look at Labtop's anhydrous NaBH4 reductive amination
procedure......this lenghtly time consuming tests are an affliction to my patience.........solo
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jon
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NaBH4 isn't very chemoselective a reducing agent if there is any potential for reversability in the reaction (ie. water is present) it will
preferentially reduce ketones to alcohols.
this can be overcome by forming the imine followed by azetropic removal of water, or treating the imine with silica prior to reduction. The best way
to form the imine would be to use alcoholic methylamine but this is a pain in the ass to make because you have to seperate out the water up a chilled
collum and then condense the methylamine seperatley or pipe it into chilled and stirred alcohol. alternately sodiumtriactoxyborohydride is much more
chemoselective but they only work at a certain PH, 6 I think.
another workaround for this is to form an intermediate from the aminocarbinol using titanium isopropoxide this forms an organometallic intermediate
like this: (CNH2O)4Ti this can then be reduced by sodium borohydride since the intermediate isn't in equilibrium.
[Edited on 2-6-2007 by jon]
[Edited on 2-6-2007 by jon]
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roamingnome
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When google patents lauched i was like a kid in a candy shop... its a bit off topic but if your patience is gone there are other reductions out
there...
Google patent search:
Patent number: 4442286
http://www.google.com/patents?id=vmQ-AAAAEBAJ&dq=4442286
not to be confused with hypophosphorous which would reduce the OH group as well....
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cool_arrow
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IMHO the imine formed from an unsubstituted ketone and primary amine is heat sensitive. If the temp. is kept 0C or lower during imine formation and
subsequent alkylation, the waxy substance can be substantially reduced.
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jon
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what do you thingk this substance is? polymerized goo? pinacols?
I know some ketones especially this one like to polymerize under basic conditions and at elevated temps.
maybe it's aldol products?
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solo
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Labtop's reductive alkylation does just that it goes overboard drying everything and the temp is kept low during the addition of the
NaBH4....will try this see if it works since it goes along with both Jon and cool arrow's suggestion............solo
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cool_arrow
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I've often wondered if the H2O removal could be dispensed with if temps. were kept cold enough during imine formation and alkylation. It would be
interesting to know.
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jon
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I think labtop's example keeps the temp low just because the reaction is exothermic.
did you see this reference??
J. Weichet, J. Hodorova and L. Blaha, "Reductive amination of phenylacetylcarbinols by sodium borohydride." Coll. Czech. Chem. Commun. 26, 2040-2044 -
CA 56, 5864c (1962)
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solo
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I had found tha ref. not long ago and asked for assistance finding it .......here is some of the response.....solo.
------------------------------------------
| Quote: |
sonogashira
posted on 28-5-2007 at 06:12 PM
Solo, here's the abstract from the article you requested (from sci-finder), hopefully it has the experimental details you're after:
Reductive amination of phenylacetylcarbinols by sodium borohydride. Weichet, J.; Hodrova, J.; Blaha, L. Vyzlumny Ustav Farm.
Collection of Czechoslovak Chemical Communications (1961), 26 2040-4
Abstract
The technologically attractive NaBH4 is a suitable agent, since no extensive racemization occurred; however, the course of the reaction was less
stereospecific than in the catalytic process with colloidal Pt to yield a mixt. of erythro and threo forms of the corresponding aminoales. in approx.
3-4:1 ratio. Thus, 7.5 g. p-fluorophenylacetylcarbinol (I)treated in 50 ml. MeOH at 0-5° with 15 ml. aq. 36% MeNH2, in 25 min. 1.5 g. NaBH4 added
portionwise, the mixt. stirred 1 hr., 5 g. K2CO3 added, excess MeNH2 and MeOH distd. in vacuo, dild. with 20 ml. H2O, the product extd. with Et2O, the
exts. dried, and satd. with HCl gave 7.1 g. crude HCl salt, m. 195-205°, which yielded 1.5 g. p-fluoropseudoephedrine, m. 114° (H2O or cyclohexane);
HCl salt m. 170° (Me2CO). The mother liquors gave 4.5 g. p-fluoroephedrine-HCl, m. 234° (90% EtOH); free base m. 76°. Similarly were obtained 5.5
g. ephedrine-HCl, m. 186-8° (base m. 76-8°) and 1.8 g. pseudoephedrine, m. 117° (HCl salt m. 164°), from 10 g. phenylacetylcarbinol (II) and 0.6
g. NaBH4, 15.6 g. optically active ephedrine-HCl, m. 216-17°, [a]20D -34°, from 15 g. (-)-II, 6.8 g. m-hydroxyephedrine-HCl, m. 183-5°, from 8.3 g.
m-hydroxyphenylacetylcarbinol (III), N-(b-hydroxyethyl)norephedrine, m. 110° (HCl salt m. 164-6°), from II and HOCH2CH2NH2, and N-butylnorephedrine,
m. 70° (HCl salt m. 219-20°), from II and BuNH2. m-Hydroxyphenylethynylcarbinol, obtained by addn. of C2H2 to m-C6H4CHO in liquid NH3, decompn. of
the mixt. with ice, extn. with Et2O, and crystn. from C6H6 gave 74% crystals, m. 101-4°. Hydration of the ethynylcarbinols according to the method of
Hennion and Fleck (CA 50, 3203c) gave 77.5% I, b8 115-16°, n20 1.5095, 66.5% II, b14 124-6°, n20 1.5330, and 90% III, m. 98° (C6H6).
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and later the full article which I'm now trying to understand with a translator and the headstart given by sonogashira with the english
abstract..........
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Nicodem
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posted on 30-5-2007 at 10:16 AM
-----------------------------------------------------------------------------------------
Reductive Amination of Phenylacetylcarbinols by Sodium Borohydride.
Weichet et al.
Coll. Czech. Chem. Commun.26 (1961) 2040-4
Here it is, fresh from the library: |
[Edited on 10-6-2007 by solo]
Attachment: Reduktive (365kB)
This file has been downloaded 3340 times
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jon
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you can download some of the trial version ocr softwayre at cnet.com
claro scan2text is good but you can only translate a page at a time so you will need adobe acrobat writer to make each page a one page pdf then you
can convert it to text and paste into babelfish.
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solo
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Try as one may, but the reductive alkylation with NaBH4 always seems to leave behind a gummy residue which interferes with recrystallation. I read
somewhere that the reductions with NaBH4 should always be alkaline to avoid the reaction with the alcohol and water, also adding additional alcohol
after the reduction to rid of the excess borane that's produced....I wonder if any of the two mentioned tips assist in the avoidance of the gummy
invader.....I guess it's worth a try .......solo
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jon
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right nabh4 reacts with water and alcohol vigorously when the ph is 6 or lower I believe. but in basic media I think something like l-pac is prone to
polymerize via an aldol condensation I think heat would speed this along in some of the exampples of nabh4 reductions water is excluded scrupulously
that means you wuold have to bubble in methylamine into dry methanol the techniches employed are to add a saturated solution of the amine
hydrochloride to caustic alkali (solid) or vise versa a saturated solution of caustic alkali to solid meNH2.hcl to produce the gas and to bubble this
into chilled methanol (stirring would help dissolution) in a beaker that's covered with a damp rag to catch any excess methylamine vapors (water
holds up to 400X it's weight in methylamine).
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bio2
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....water holds up to 400X it's weight in methylamine).....
40% Methylamine in water is concentrated right?
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jon
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maybe a typo but the principle works with the rag over the beaker it keeps the stench down.
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guy
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I thought that NaBH4 was not a good reducing agent for imines because it's too powerful and reduces the ketone/aldehyde first.
I think NaBH3CN is better.
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