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Sauron
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I finally found a better route to p-nitrobenzyl bromide that avoids the various problems of the other routes.
The problem with nitration of toluene is tedious workup only. Then for some people elemental bromination might be a problem but not for me.
The better method is nitration of benzyl acetate as described by Hurd et al in J.Org.Chem. 12, 369 (1947) The p-nitrobenzyl acetate is isolated in 36%
yld after two recrystallizations. The o-isomer remains in mother liquor and can be recovered.
The ester is then saponified with hot methanolic NaOH by an Org Syn. method (CV 3, 652). The p-nitrobenzyl alcohol (which is costly to purchase, and
unavailable by nitration of benzyl alcohol) can then be brominated by conc HBr, or by NaBr/H2SO4, or by TCT/DMF/KBr, PBr3, etc. Cf. Norris, Watt, and
Thomas, JACS 38, 1077 (1916) for HBr methos, 3.3 g acid per g alcohol, but quantitative yld.
So, three steps from cheap benzyl acetate rather than two steps from toluene but involving more hassles.
If anyone would like the Org.Syn. and/or JACS articles Ill post them.
This alcohol has also been prepared by electrochemical means (Elbs, Ber. (Ref.), 29, 1122 (1896) and chemical means
(Dieffenbach, Ger. pat. 214,949 [Frdl., 9, 156 (1908–10)]. I admit I have not examined these, because of my poor German skills and skittishness re
patents, and I am satisfied with the straightforwardness and simplicity of the route outlines above and the good details of procedure and yield at
each stage. There are no expensive or exotice reagents to obtain (or unobtain.)
[Edited on 12-4-2007 by Sauron]
Attachment: jo01167a002[1].pdf (291kB)
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Klute
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I beleive Benzylacetate is easily made in high yield with anhydride acetic, but can surely also be prepared by using GAA, H2SO4 in a Dean Stark trap
or with other means of deplacing equilibrium...
That considerably simplifies the preparation.. Thanks Sauron!
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Sauron
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True, but it's about same price as benzyl alcohol. The Vogel procedure from the alcohol, GAA and a little sulfuric catalyst is not very high yld
(looks like <50%) Clearly AcCl or Ac2O will work better but why waste them on a cheap commoditized ester? I'll just buy it. Also it's pretty high
boiling so any distillation to purify it will need to be in vacuo or else you need to interpose an air condenser before the water cooled condenser or
risk cracking the Pyrex.
If you really want to prepare the benzyl acetate then there's the available route of making benzyl chloride from benzyl alcohol and TCT (CC). Simply
mix 6 mols of the alcohol to 1 mol of the chlorinating reagent (no other solvent, the excess alcohol serves for that) and reflux for 60-120 minutes,
yield 72%
If 72% isn't good enough then you prepare the TCT/DMF complex and react that with benzyl alcohol, this gives 98% yield in 15 minutes! Benzyl bromide
can also be prepared this way by addition of KBr to the reaction. For details see attachment. (room temp, DCM solvent, 1:1 mol eq)
The lit says benzyl bromide can be nitrated but I am unable to obtain the article in Bull Soc Chim (not sure Fr or Belg) from 1921, so I have no
details. I may go experimental and work this out, which would make the target p-nitrobenzyl bromide available in two steps from benzyl alcohol. I have
lots of TCT and no problem buying more. However this happy situation does not apply to a lot of our vrethren in Europe.
As I now have the mp of p-nitrobenzyl bromide (mp 99-100 C) maybe the nitration will be facile like it is for benzyl acetate.
To make the benzyl acetate from benzyl chloride you react it with sodium acetate in AcOH, the Org.Syn. procedure is given for the nitrated benzyl
chloride, and is 80% yld. This is a lot better than Vogel's sulfuric acid catalyzed esterification of the alcohol with acetic acid (q.v.) which is
less than 50%.
[Edited on 13-4-2007 by Sauron]
Attachment: TCTDMF.pdf (55kB)
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Sauron
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We have been working on the assumption that benzyl alcohol would not survive the conditions of aromatic mononitration; this turns out to be erroneous.
Benzyl alcohol can be nitrated to a mixture of isomeric, principally o- and p-nitrobenzyl O-nitrates. (nitrophenyl nitroethers)
These in turn can be hydrolyzed to the alcohol, displaced to nitrobenzyl acetates, or the nitro group can be displaced by halogen via NaX/KX in
acetone, all of these reactions are high yield.
Given the moderate yield (50-60 %) of the NaOH saponification of p-nitrobenzyl acetate to the corresponding alcohol, the selection of starting
material is now an open question.
Benzyl acetate is significantly cheaper than benzyl alcohol but this is offset by the losses in saponification unless one's final target is the
nitrobenzyl ether.
If the target is the nitrobenzyl bromise or chloride then there are two available two-step routes:
nitration of benzyl alcohol then displacement of nitro group with alkili halide
Or
Halogenation of benzyl alcohol then nitration
The nitration of benzyl acetate is done with mixed acids. The nitration of benzyl alcohol is done with fuming nitric acid (d.1.5) with NOx removed by
urea and chilled to -10--15 C.
Syntheses of organic preparations and intermediate products based on nitrate esters
P. M. Kochergin and L. S. Blinova
Journal: Pharmaceutical Chemistry Journal
Issue: Volume 1, Number 1 / January, 1967
Pages 5-7
also follow-on article in Number 2.
[Edited on 15-4-2007 by Sauron]
[Edited on 15-4-2007 by Sauron]
Attachment: nitrobenzyl nitrate.pdf (234kB)
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Ozone
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Sauron,
Here's a neat paper for your toilet-reading enjoyment:
Oxidation of Aromatic Amines with Hydrogen Peroxide Catalyzed by
Cetylpyridinium Heteropolyoxometalates
This looks quite tweakable, selective and in most cases mild. Yields on nitrotoluene were quoted ~92%.
Cheers,
O3
Attachment: Sakaue 1992.pdf (805kB)
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-Anyone who never made a mistake never tried anything new.
--Albert Einstein
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Sauron
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Thanks @O3. I dunno where I can get 35% h202 in Thailand. This is one to file away in case I come into some p-toluidine. Also working up from 3 mmol
scale to a Kg of purif product is sometimes a pain.
For immediate purposes I think I will stick to benzyl alcohol nitration, the lit. has this on a 200 g purified product scale.
Call me timid but don't call me late for lunch!
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garage chemist
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The workup of the toluene nitration sounds somewhat more tedious than it is. The freezing will only have to be done 2-3 times to get a good separation
(depending on the column), and the recrystallization of p-NT from EtOH/H2O may only have to be done once if done well.
If p-nitrobenzyl bromide is the desired product, I would also choose to go with the toluene nitration. May I ask what the p-nitrobenzyl bromide is
needed for? I dont know any uses for this substance right now.
O-nitrotoluene is useful as well, not only for o-toluidine, but also for e.g. anthranilic acid, or 2-halotoluene, or 2-substitued benzoic acids and
benzaldehydes.
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Sauron
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@gc, thanks. The target compound and its close relatives
p-nitrobenzyl alcohol
p-nitrobenzyl acetate
p-nitrobenzaldehyde
have some importance in medicinal chemistry including anticancer drugs.. The alcohol and bromide also are used as protecting reagents in peptide
synthesis, in which I am much interested.
The bromide is used in qualitative analysis of carboxylic acids
Klute and I are messing around with a process for seperating isomeric phthalic acids. He wants to oxidize mixed toluenes, and these esters are my
suggestion for how to seperate the acids produced, by vacuum distillation.
[Edited on 16-4-2007 by Sauron]
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