hypo (Official Hive Approximator)
07-24-02 07:32
No 336565
      questions on the alkylation of phenols  Bookmark   

hi,

i have two questions concerning the alkylation of phenols:

1) shulgin alkylates homo-syringonitrile with EtI and K2CO3 in acetone.
will this form the insoluble potassium salt of the phenol, which is slowly
alkylated by EtI into the 4-ethyl homologue, which is soluble in acetone?
or is it the soluble homosyringonitrile (can you call that a free acid?) which
is alkylated?

2) using the finkelstein reaction and the right solvent, wouldn't it be
possible to use EtBr and catalytical amounts of KI, which would give EtI
and on alkylation KI, which would again give EtI and so forth?
 
 
 
 
    Osmium
(Stoni's sexual toy)
07-24-02 08:15
No 336573
      1) it's always the phenolate that is alkylated, ...  Bookmark   

1) it's always the phenolate that is alkylated, not the free phenol (higher nucleophility of the phenolate).

2) it doesn't matter if you use alkyl chloride, bromide or iodide, they will all alkylate the phenolate. Iodide will be faster and maybe a bit higher yielding than the others, but the differences aren't very big. No need to convert EtBr into EtI first. The reason alkyl iodides are preferred most of the time in the lab is reduced volatility, not higher reaction rate.

I'm not fat just horizontally disproportionate.
 
 
 
 
    hypo
(Official Hive Approximator)
07-24-02 08:32
No 336576
      thanks!  Bookmark   

thanks!

the answer to the second question makes me happy. twice
the amount of EtBr is still way cheaper than EtI (for me).

i have another question (doh!): is there any reason why
5-iodo-vanillin could not by alkylated on the 4-position?

i understand that the iodine rest is a huge polarisable
electron balloon, but i don't know what consequences this will have...
 
 
 
 
    tiresias3
(Stranger)
07-24-02 15:58
No 336709
      The 4-iodo substituent should bee inconsequential ...  Bookmark   

The 4-iodo substituent should bee inconsequential to the etherization of the 4-phenolate of vanillin.  However, you could simply alkylate the 4-position first and iodionate the 5-position second, although the ring would be less activated in the second reaction sequence and thus less amenable to electrophilic aromatic substitution.
 
 
 
 
    hypo
(Official Hive Approximator)
07-25-02 00:47
No 336871
      good.  Bookmark   

> The 4-iodo substituent should bee inconsequential to the etherization of the 4-phenolate of vanillin.

that's great, thanks.

> However, you could simply alkylate the 4-position first and iodionate the 5-position second,

the problem here is that vanillin iodination is conveniently
done with NaI/I2 in basic aqueous solution. i guess the 4-alkyloxy
compound would not be soluble in this medium and as you say much
less activated (the reason for the stability of phenolates is
that they give their negative charge to the ring...). so i'm
not sure that would work...
 
 
 
 
    Rhodium
(Chief Bee)
07-25-02 11:52
No 337003
      Electrophilic aromatic substitution theory  Bookmark   

3,4-dialkoxybenzaldehydes are halogenated in the 6-position, the reason that vanillin itself is halogenated selectively in the 5-position is that the free OH is very strongly ortho-directing (as its para position is already taken).

When halogenating a 3,4-dialkoxy-benzaldehyde, the ortho/para-directive effects are selective towards para-substitution, and only a little towards ortho-substitutions.

See ../rhodium/chemistry /tma2.vanillin.html for example. There might be halogenating agents which are ortho-selective, but I don't know of any such reagents.
 
 
 
 
    hypo
(Official Hive Approximator)
07-25-02 13:12
No 337048
      para direction stronger than ortho?  Bookmark   

> 3,4-dialkoxybenzaldehydes are halogenated in the 6-position

well, this is a good thing! it means TMA-2 and TMPEA analogs from
vanillin! (too bad shulgin wasn't very successful with them...)

but it makes me wonder: the 6 position is disfavored by the formyl
group. so para direction is notably stronger than ortho. this can
not be explained by the resonance structures. is this a simple +I
effect of the oxygen or something more complicated?

official gene trash
 
 
 
 
    neuromodulator
(Hive Bee)
07-25-02 16:19
No 337100
      If you want to make TMA-2 or MEM from vanillin...  Bookmark   

Then I would suggest alkoxylating the 4-phenol, condensing with nitroethane, reducing to the 1-(2-aminoisopropyl) derivative, protecting the primary amine, and then brominating (or iodinating as the case may be).  The methylene unit will aromatically favor then bromination of the #6 position, while the benzaldehyde would rather strongly work against it.  However, I think 3-methoxy-4-ethoxy(meth)amphetamine or 3,4-dimethoxy(meth)amphetamine would be more exciting to make than either TMA-2 or MEM because their pharmacology is virtually unexplored in humankind (as far as I can tell anyway) in comparison with the latter two PEA's.  Why not make all 6?
 
 
 
 
    moo
(Hive Bee)
07-25-02 16:58
No 337121
      iodide/iodine iodination  Bookmark   

I read somewhere that only phenolates could be iodinated with plain I2 and that the iodide in the vanillin iodination procedure was there to get I2 dissolve in water as the triiodide ion. On the other hand ICl can be used on less activated substrates, so maybe the reaction in Post 198306 (foxy2: "Iodination of Vanillin", Chemistry Discourse) is another version of the same idea.
 
 
 
 
    hypo
(Official Hive Approximator)
07-29-02 06:34
No 338516
      help needed!  Bookmark   

thanks for the suggestions bees, but before dreaming of
obscure analogs, the alkylation must be made to work tongue

two experiments with basically the same results were made. the difference was only
the longer reflux time of the second one.

i'll only describe the second one:

actone was stirred for 20h over anhydrous CuSO4 with the problems mentioned in Post 336535 (hypo: "grey CuSO4 ???", Chemistry Discourse).
about 25 ml of this acetone was distilled off and 1 g 5-iodo-vanillin (non recrystallised,
mp 175C) was added under stirring. the 5IV dissolved nearly completely giving a reddish solution.
1 g anhydrous K2CO3 was added. after a short time a skin coloured (if you are caucasian)
precipitate formed. to this was added 1.7g EtI and the mixture was refluxed for 16 h. an
TLC was taken with inconclusive results, so another 0.8g EtI was added and the
reaction refluxed for another 24 h, when another TLC was taken with the same inconclusive
results. During the whole 40 h, the reaction did not change in appearance at all!
after cooling to room temperature, it was diluted with ether and the solids filtered off.
the solids were taken up in water, a tiny amount of gakk filtered off and the aqueous
solution acidified with 30% HCl. there was only very little precipitate (wich is probably
a good thing!). the ether/acetone was removed from the organic filtrate by distillation
and the residue (a yellow oil) taken up in a small amount of ether (it is very soluble
in ether!). this was then washed twice with Na2CO3 solution (to remove phenols and
carboxylic acids), dried over Na2SO4 and the ether removed by distillation. this
left a small amount of a yellow viscous oil, which gets hard in the freezer, but
does not crystallise.

i suppose that the oil does not crystallise, because there is still EtI in it.
how would you get rid of it, without sucking it into the oil pump??

if this turns out to be low yielding / total bunk, the only idea i have is
to use more solvent or another solvent (maybe there is solvation issues)
resp. more EtI...

official gene trash
 
 
 
 
    Osmium
(Stoni's sexual toy)
07-29-02 07:44
No 338531
      > this was then washed twice with Na2CO3 ...  Bookmark   

> this was then washed twice with Na2CO3 solution (to
> remove phenols and carboxylic acids)

I'd rather use diluted NaOH.

> i suppose that the oil does not crystallise, because
> there is still EtI in it.

Unlikely.

> how would you get rid of it, without sucking it into the
> oil pump??

Its boiling point is so low that you can suck it right through the (pre-warmed!) pump without doing any damage.
Recrystallise your product, e.g. from MeOH, or MeOH/hexane

> if this turns out to be low yielding / total bunk,

Again, unlikely.
I seem to remember that the iodination reaction doesn't go to completion, so you most likely ended up with a mixture of the methylated vanillin and 5IV. Did you do a TLC on all precursors/products?

> the only idea i have is to use more solvent or another
> solvent (maybe there is solvation issues) resp. more EtI...

Shulgin uses KOH/EtOH all the time. Might wanna try this out.



I'm not fat just horizontally disproportionate.
 
 
 
 
    hypo
(Official Hive Approximator)
07-29-02 10:22
No 338589
      thx.  Bookmark   

> I'd rather use diluted NaOH.

ok, next time.

>  Its boiling point is so low that you can suck it right
> through the (pre-warmed!) pump without doing any damage.

hmm.. 72 is that low? that would mean sucking DCM or ether
through it wont be a problem either (as long as you condense
the vapors on the exhaust of the pump)?

> Recrystallise your product, e.g. from MeOH, or MeOH/hexane

ok, this will be done if it doesn't crystallise overnight
(the first batch didn't). the problem is that the melting
point is probably rather low. veratraldehyde melts somewhere
in the 40ies, the ethyl will lower it a bit and the iodine higher
it a bit, so expect something in the 30-50 region. sounds
like an oil out candidate!

> Did you do a TLC on all precursors/products?

the chemist just used his last 3 TLC-plates (seems like he has
to pay his lab supply a visit again!) and did 3 TLCs with
Tol/EtOH 6:1 and a small iodine crystal to develop them, giving:
product: one spot Rf=0.47
5-iodo-vanillin: one spot Rf=0.35; maybe a spot Rf=1.0 (it's hard to tell, iodine always colors the solvent front, this time there was a little spot at the front)
vanillin: one spot Rf=0.36

seems like the choice of solvent was not good. nearly no difference in Rf
between vanillin and 5IV

> Shulgin uses KOH/EtOH all the time. Might wanna try this out.

huh? i dont understand. do you suggest using KOH/EtOH as solvent for
the alkylation? wouldn't this hydrolise the alkyl iodide?
or did you mean to purify the EtOH with KOH?

i was thinking more in the direction of EtOH(dried over CaO)/K2CO3 or
DMF(dried over MgSO4)/K2CO3

official gene trash
 
 
 
 
    hypo
(Official Hive Approximator)
08-03-02 11:18
No 340658
      suggestion for rextallisation solvent?  Bookmark   

hi again,

recrystallising from methanol didn't work that well, the stuff is much
too soluble in MeOH! some solid could be isolated, but very off-white
and not really crystalline, rather pasty. a really fast mp test showed
an mp in the 50ies (C).

yield was not good (in the 50% range), but that can be worked on.

so, anyone got an idea what could be a good recrystallisation solvent
for 4-ethyl-3-iodo-5-methoxy-benzaldehyde??

couch terrorist
 
 
 
 
    Osmium
(Stoni's sexual toy)
08-04-02 00:11
No 340990
      Hexane  Bookmark   

Hexane

I'm not fat just horizontally disproportionate.
 
 
 
 
    hypo
(Official Hive Approximator)
08-05-02 10:10
No 341716
      shit!  Bookmark   

hexane is not available, so 2 different petroleum fractions
were used (naptha and kerosene). dissolve in warm solvent
and put in freezer. same result: first some red oil crashes
out (product + impurities???), then white crystals.

the back of the crystals is full with the oil, so separation
is impossible.

only idea i have: wait until most of the oil crashed out,
decant and repeat....

frownfrownfrown



(excuse the bad image manipulation skills)


couch terrorist
 
 
 
 
    Osmium
(Stoni's sexual toy)
08-05-02 15:47
No 341855
      When an oil crashes out the solvent is too ...
(Rated as: excellent)
 Bookmark   

When an oil crashes out the solvent is too non-polar. Try a solvent mixture, like 50:50 IPA/alkane. Or acetone/alkane.

I'm not fat just horizontally disproportionate.