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Sauron
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DJK
No need to be concerned about competing alkylation in the F-C acylationof benzene with a-chloropropionyl ch;oride.
The well known tear gas CN, chloroacetophenone, is manufactured by same reaction using chloroacetyl chloride. No alkylation product forms (which would
be phenylacetyl chloride.)
Phenacyl bromide, military tear gas, is made in identical fashion from bromoacetyl bromide (or chloride.)
By analogy 2-chloropropionyl chloride ought to acylate benzene just fine.
The initia; product will be a chloropropiophenone, and probably lachrymatory.
Hydrolyze the chlorine. Oxidize to the same product that would have been obtained from acylation with pyruvoyl chloride.
Finally, reduce the benzilic carbonyl to hydroxyl. Same as required with product of abylation with pyruvoyl chloride.
Voila. Racemic PAC.
No expensive pyruvic acid
No oxalyl chloride
No -50 C
Nothing for hector to kvetch about.
He can start with propionic or lactic acid, whichever is cheaper in Iran. Makes no difference to me.
He will need to resolve the DL-PAC to an ee at least as good as the biotech product, c.90% L-PAC Fractional crystallization of a chiral ester, or
prep scale chiral HPLC. Fat chance of the latter.
A piece of cake.
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hector2000
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Mr Sauron,
Now i want to do lactic acid method and then test result with GC-MS
And this is interesting for me that know reaction between Lead Acetate(II) and Mandelic Acid and
Sure i will try it and test with gc-ms again.
Ok let Review:
1-I will do reaction between lactic acid and HCL or PCL5?
2-After making chloropropionyl chroride then i should react it with benzene
3-Finally Hydrolyze result
Also i find 2-chloropropionyl chloride here
Just react it with benzene in FC?
If everthing is ok i tyr it now.
[Edited on 30-4-2009 by hector2000]
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Sauron
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OK you can buy 2-propionyl chloride
Make sure that is CH3-CH(Cl)-COCl and NOT Cl-CH2-CH2-COCl
a-chloroprionyl chloro, NOT beta-chloro!
As I stated above this is a Fridel Crafts acylation so study the appropriate reaction consitions, solvent, temperature and time. The catalyst is
anhydrous AlCl3.
I can tell you, add the acid chloride slowly to the benzene and AlCl3 at 25 C with stirring and then reflux at 60-70 C 2 hours.
Filter the liquids from the catalyst in a fuume hood and strip off the solvent then distill in vacuo. Purify by steam distillation.
What you have at that point is Ph-C(O)-CH(Cl)-CH3
Treat with hot aqueous sodium carbonate to hydrolyze.
Niw oxidize to the diketone
Ph-C(O)-C(O)-Me
This is same as what you would get with pyruvoyl chloride
Finally reduce the first C=O closest to ring
Ph-CH(OH)-C(O)-Me
An equal mixture of D-PAC and L-PAC
You must separate these by special means
Is all that clear?
If you do not buy the chloropropionyl chloride, my advice is make it from propionic acid not lactic acid
Lactic acid will give you trouble!
A-chlorinate with N-chlorosuccinimide in CCl4
Then make the acyl cholide with SOCl2 (thionyl chloride)
Then distill.
No solvent needed for SOCl2. Use a 5% excess.
[Edited on 30-4-2009 by Sauron]
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hector2000
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Thanks Mr Sauron,
After react Ph-C(O)-CH(Cl)-CH3 with sodium carbonate i will have Ph-C(O)-C(O)-Me ?
How reduce the first C=O closest to ring?
I found old merck 2-propionyl chloride(820333) here.
If pac produce then i will make 2-propionyl chloride.
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Sauron
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Just read my posts above, I have spelled it out for you TWICE but you continue to skip the oxidation step\
Step 1 Friedel Crafts
Step 2 Hydrolyze -Cl to -OH classically hot aq Sod.carbonate
Step 3 Oxidize C2 -OH to C=O classically SeO2
Step 4 Reduce C1 carbonyl to OH NaBH4 suggested upthread
This is your reaction, not mine, it is up to you to select reagents and consitions and search the literature. NOT my job. You have tested the limits
of my patience.
2-chloropropionyl chloride is CAS Registry # 7623-09-8
[Edited on 30-4-2009 by Sauron]
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DJF90
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Would NaBH4 reduction predominantly reduce the C1 ketone? Also use of another oxidant (SeO2 isnt exactly nice stuff, maybe that was the point  )?
If I were to do this sythesis, I think this would be the route I would choose:
> Oxidise lactic acid with acidic dichromate (to pyruvic acid)
> For the acetal using ethylene glycol and toluene as the solvent with a dean stark trap.
> Base hydrolysis of the ester that may have formed (acetals are stable to basic conditions) with NaOH
> Form the acyl chloride of the protected sodium pyruvate with thionyl chloride.
> Do a Friedel-Crafts reaction of the acyl chloride on benzene using anhydrous AlCl3
> Reduce the C1 carbonyl with NaBH4, the C2 carbonyl is protected.
> Deprotect the C2 carbonyl by acid hydrolysis with excess water. This should yield l-PAC.
[Edited on 30-4-2009 by DJF90]
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Sauron
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DJK, what makes you think SOCl2 will succeed in making pyruvoyl chloride?
Have you read the Oth Syn prep of same?
Phosphorus chlorides failed. Phosgene and ocalyl chloride give very poor yields.
Only one reagent works well on pyruvic acid, that is 1,1-dichloromethyl methyl ether made from methyl formate and PCl5,
But workup requires dry ice-acetone temps in fractionation and hector balks.
The pyruvoyl chloride can also be made by treating trimethy;silyl chloride with pyruvic acid and TEA to obtain TMS-pyruvate, then treating that with
oxalyl chloride in Et2O.
In short, the lit. does not support use of SOCl2, so it is wishdyl thinking to blithely assert it is possible without trying.
SeO2 is not so bad. It is reagent of choice for vic.dicarbonyls and tricarbonyls. It is solid and easily dispensed, removed and dispoaed of.
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DJF90
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Sorry sauron, didnt look at the pyruvoyl chloride prep. Seeing as there is not actually a carbonyl in the alpha position (as it is protected) then
perhaps SOCl2 will still work?
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Sauron
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"Perhaps" covers a multitude of errors. I can think of a dozen reagents for acyl chlorides not mentioned in the two papers I posted, that "perhaps"
might work. I fasil to see the logic of assuming that protecting the C2 carbonyl with a ketal will make a difference in the efficacy of SOCl2. I do
not know why SOCl2 fails and therefore do not think we have sufficient info to base any tactic to make it work.
Besides, ketals are acid labile, SOCl2 breaks down to SO2 and HCl and so will probably deprotect that carbonyl.
All in all, if you want to make a research project out of this, fine, but I's recommend taking the safer route, forget SOCl2. I do not see why
pyruvoyl chloride has any advantage over 2-chloropropionyl chloride in the F-C acylation. I already answereede your cibcern re competitive alkylation.
2-chloropropionyl chloride is a one carbon homolog of chloroacetyl chloride, which works just fine in this reaction, see chloroacetophenone in
Sartori's THE WAR GASES in forum library (CN tear "gas")
From a-chloropropiophenone to DL-PAC is simple. If you want to explore alt. reagents to the ones suggested feel free, but it is really Hector's
headache and not mine. He is annoyingly obtuse.
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hector2000
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Thanks everybody that guide me in this Topic(Special thanks of Mr.Sauron and panziandi)
Soon i will post GC-MS Result
[Edited on 30-4-2009 by hector2000]
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Sauron
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According to a current (April 2009) paper in JOC, a-ktoacid chlorides react with alkylstannanes such as phenyltributyltin or methyltributyltin to give
1,2-diketones
Ph-CO-CO-Cl + MeSnBu3 -> Ph-CO-CO-Me
Furthermore, the stepwise reaction of oxalyl chloride can be used to form the required a-oxoacid chloride in situ
Note that is the organostannanes are phenyl and methyl, respectively, the product will be identical to the F-C acylation product of pyruvoyl chloride
and benzene (or that of 2-chloroproionyl chloride, after hydrolysis and oxidation.)
Any experience with organometallic synthesis, hector? Like a ?Grignard or lithiation?
Synthesis of 1,2-Diketones by the Transition Metal-Catalyst-Free Reaction of α-Oxo Acid Chlorides or Oxalyl Chloride with
Organostannanes
Taigo Kashiwabara and Masato Tanaka*
J. Org. Chem., Articles ASAP (As Soon As Publishable)
Publication Date (Web): April 9, 2009 (Note)
DOI: 10.1021/jo802814r
The reaction of an α-oxo acid chloride with an organostannane proceeds transition metal-catalyst-free to afford a 1,2-diketone in an excellent
yield. In addition, a sequence comprising pretreatment of oxalyl chloride with an organostannane and a ...
The full text is now available in References
[Edited on 30-4-2009 by Sauron]
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DJF90
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Yes I had thought of the acid hydrolysis of the ketal by the products of acyl chlorination, but there shouldnt be any HCl formed as I suggested the
use of the Na salt, and as there should be no water in the reaction medium (SOCl2 is hydrolyses, as well as the acyl chloride product) then hydrolysis
should not occur? At least that was my logic anyway. But now I see that getting the anhydrous solid from the solution in the previous step may be a
real pain in the ass. Looks like hector's got some kind of result...
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hector2000
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unfortunately No but i am ready for Learn about making it. 
I have suggestion(100% wrong but better i say it)
May we use Trimethylaluminium instead of methyltributyltin?
I know trimethylaluminium is dangerous but this is just suggestion and i wont do this reaction.(I said this suggestion because i found
trimethylaluminum here(in iran))
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panziandi
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Hector:
Grignards and organolithiums are on one level
Trialkylaluminiums are a whole different ball game! - Don't bother contemplating these unless you are MORE than competent with handling
organolithiums, schlenk techniques and glove box manipulations etc.
And no, I doubt they will work, tin compounds would be much nicer to work with IMHO. You can make them from Grignards (or from organoaluminiums if you
are competent) and the tin halides.
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Sauron
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Forget organoaluminums.
1. They burst into flame on contact with air
1. They cannot be substituted here
In marked contrast to many organometallics, tin alkyls and aryla are stable to air and water and available commercially as neat liquids of relatively
low price rather than as dilute solutions in solvents.
The key compound is tri-n-butyltin chloride Sn(nBu)3Cl prepared from 3 mols of nBuMgCl and anhydrous SnCl4.
This is then reacted with phenylmagnesium chloride to afford PhSN(nBu)3, or MeMgCl to obtain MeSn(nBu)3.
These are then reacted stepwise with oxalyl chloride to form PhCOCOMe
Reduce the C1 carbonyl and you have DL-PAC.
We mine tin in Thailand and Malaysia. Good to know it is good for something other than cans.
[Edited on 1-5-2009 by Sauron]
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hector2000
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Really interesting method
But i should prepare nBuMgCl(because i didnt find it here)
I think nBuMgCl prepare from 1-chlorobutane+Mg
May i prepare MeMgCl same?(methyl chloride+mg?)
I have another suggestion(again wrong):
A after react oxayl chloride with benzene in FC may below reaction happen?
Ph-(C=O)-(C=O)-Cl+LiCH3(Methyllithium)-->Ph-(C=O)-(C=O)-CH3+LithiumChloride
[Edited on 1-5-2009 by hector2000]
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Sauron
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Yes you could react (COCl)2 with benzene and AlCl3 catalyst, preferably in CS2 solvent below room temperature.
Yes that would give you Ph-COCOCl
And yes you can then react that with MeSn(nBu)3
You make an ether or THF soln of nBuMgCl by reacting nBuCl with Mg turnings in DRY ether and then you add SnCl4 also anhydrous, 1 eq to 3 eq of the
nBuMgCl. MgCl2 will be by product
You work up the product and can isolate and distill the nBu3SnCl.
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panziandi
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To avoid any mishaps, could you not make the nBuMgCl then add SnCl4 to prepare the nBu3SnCl then add a solution of MeMgCl in order to obtain
MeSn(nBu)3, then work up that. Avoids manipulating the nBu3SnCl intermediate and prepares the desired final compound in one pot?
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Sauron
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The organotin compounds are all stable to air and water, non pyrophoric, isolable as neat liquids, and commercially available as such.
So just what sort of mishaps are we avoiding?
The normal rules of organometallic prep do not appear to apply to trialkyltin halides or tetraalkylstannenes.
Here is an Org Syn prep of a tributyltin alkyl formed from tributyltin chloride and a Grignard formed in situ from the alkyl chloride and Mg turnings
in THF under N2 atmosphere and with ultrasound assistance in mixing.
From this we are told that tribubtyltin compounds smell bad and are toxic. The toxicity I knew about; odor I did not Tetramethyl and tetraethyltin
are described in Brauer as having pleasant ethereak aromas. Go figure. Use a hood and gloves.
Attachment: CV9P0707.pdf (173kB)
This file has been downloaded 1042 times
[Edited on 1-5-2009 by Sauron]
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panziandi
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Well... it's one less step, avoids having to work up and isolate an intermediate if it's possible to do it in several steps in one pot then you should
avoid mechanical losses etc.
Besides it is hector to whom you propose this reaction 
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Sauron
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nBu3SnX (X=halide) is the common intermediate for both the phenyl and methyl derivatives.
My surmise therefore is that it will either be purchased or prepared in relatively large amounts and stored for dispensing as needed.
While the price is not too onerous $165 US/500 g, about 1,5 mol) it can certainly be prepared for far less (nBuCl, SnCl4, Mg, Et2O or THF)
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hector2000
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I fount Tributyltin chloride(CAS#1461-22-9)here(20$ for 100ml)
Just i should react it with MeMgCl.
I should do special work for this reaction?
I should distil final product?
Final Problem is Prepare MeMgCl(because Mecl is gas and this is difficult to controll it)
but cholorobenzene(phenyl chloride) is available and cheap
Reaction between Ph-(CO)-(CO)-Cl and PhSN(nBu)3 will Produce DL-PAC?
[Edited on 1-5-2009 by hector2000]
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Sauron
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Quote: Originally posted by hector2000  | I fount Tributyltin chloride(CAS#1461-22-9)here(20$ for 100ml)
Just i should react it with MeMgCl.
I should do special work for this reaction?
I should distil final product?
Final Problem is Prepare MeMgCl(because Mecl is gas and this is difficult to controll it)
but cholorobenzene(phenyl chloride) is available and cheap
Reaction between Ph-(CO)-(CO)-Cl and PhSN(nBu)3 will Produce DL-PAC?
[Edited on 1-5-2009 by hector2000] |
You have to understand what you are doing and prepare yoursekf by studying the reactions involved and examples of procedures from the literature.
Yes you will react nBu3SnCl in ether or THF with MeMgClin same solvent, DRY and under N2.
You cannot replace MeCl with Ph Ck
If you do you will have PhMgCl NOT MeMgCl
If you react PhCOCOCl with PhSnnBu3 you will not get PhCOCOMe
You will get PhCICOPh and that is NOT what you want
MeCl dissolves in ether
Read aboutGrignard reaction
Activate youur Ng in ether with a small crystal of iodine
Make the ether as cold as you can (ice/salt bth) and bubble in MeCl till all Mg dissolves
Or BUY methylmagnesiumchloride solution in ether or THF
I can't do the reaction for you, hector.
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Sauron
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One mol CH3Cl weighs 50 g
So you can dissolve MeCl gas in cold ether or THF and measure by weight
In one liter of cold ether add enough MeCl gas to cause a weight gain of 50 g
Obviously flask, ether etc must be on a balance or electronic scale
Not so hard.
Keep soln cold and tightly closed and refrigerate (explosion proof lab freezer)
You could also use methyl iodide which is a liquid (iodomethane)
Buy it or make it from methanol, I2 and a little red phsophorus as in Org.Syn.
In the forum library are many books on practical organic chemistry - lab manuals. Bogel, Gattermann, Cohen, Shirley etc. In EVERY book there will be
at LEAST ONE detailed description of Hrignard reaction:
How to prepare Grignard reagents
How to conduct reaction
How to work up product
STUDY THESE
Go to the Organic Syntheses website, again many many detailed Grignard preparations.
STUDY THESE
and I will post some organotin preps
My advice is PRACTICE Grignard reactions, do some simple ones. Get some experience eith alkyl and aryl magnesium halide solutions.
Buy some anhydr SnCl4 (Tin (IV) Chloride
I will post prep for tetramethyltin and tetraethyltin. PRACTICE THESE. If you can make these you can make tetrabutyltin.
Tetrabutyltin (nBu4Sn) reacts with 1 eq iodine to ptoduce nBu3SnI and nBuI. You can make your own tributyltin iodide
I don't know how you were trained as a chemist without lwarning these but TEACH YOURSELF. I am too far away to coach you much.
[Edited on 2-5-2009 by Sauron]
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Sauron
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Here are the preps from Brauer
Prep of MeMgBr from MeBr gas and Mg in dry Et2O (doethyl ether) and use of that to react with SnCl4-etherate (NOT SnCl4 directly but its addition
compound with Et2O) to produce Me4Sn
And same prep for Et4Sn from ethylmagnesium halide
Practice with these and you will be ready for nBu3SnMe
Attachment: Pages from brauer_ocr.pdf (101kB)
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