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Finkelstein Swap?

Globey - 4-4-2009 at 09:22

Hi,
I'm making a request for an actual practicle procedure, partly because of time constraints (only had time to browse Vogels). So please don't be snotty! J/K

So thanks in advance =)

What I want to do, is start from cinnamyl chloride, and do a Finkelstein type swap with bromine. The alkene might already have the reactivity I want, but bromine will leave quicker. Assuming the alkene in DMSO and add some NaBr? If someone could post the actual procedure, it would be most appreciated. Every time I looked it up here, I just saw ref. going from bromide to iodide, but in theory, chloride to bromide would work as well (not as well, but in addition too). Many thanks

[Edited on 4-4-2009 by Globey]

solo - 4-4-2009 at 10:27

......chlorine to Iodine can be seen here, hence similar approach can probably be used for Chlorine to Bromine......solo

http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/d...

...also something here about it,

http://www.psychonaut.com/index.php?option=com_forum&pag...

[Edited on 4-4-2009 by solo]

Arrhenius - 4-4-2009 at 11:12

In theory chloride to bromide wouldn't work very well. The reaction is entropically driven because sodium iodide is soluble in acetone, whereas sodium bromide (product) is not.

Typical procedure is to reflux in acetone with excess NaI, followed by aqueous workup.

[Edited on 4-4-2009 by Arrhenius]

Ebao-lu - 4-4-2009 at 11:15

I've seen several mentions that in acetone this swap works fine only for NaI, and NaBr does not work (prob. due to poor solubility). Maybe in other solvents it will. What is the problem with using NaI?
Another possible method (take into consideration) is with PTC and HBr. J. Chem. Soc. Perkin Trans. 1, 1992, p. 2309, "Finkelstein reaction with aqueous hydrogen halides efficiently catalyzed by lipophilic quarternary onium salts" Unfortunately, i dont have access there, but the procedure should definitely be given there

[Edited on 4-4-2009 by Ebao-lu]

DJF90 - 4-4-2009 at 11:29

You could theoretically use NaI in acetone with your substrate, seeing as you only want to increase the reactivity... I suppose the only prevention is the high cost of the NaI.

Globey - 4-4-2009 at 11:49

Thanks all for the advice. I'll look up perhaps KBR is more soluble in DMK than Na? It's either spa salts or Kodak photography grade. The original procedure calls for using the alkeyl bromide, so was just trying to follow it as closely as possible. Wonder if substituting chloride (when bromide is called for) would work. Perhaps just increased rxn time? Wonder if iodide would present some unanticipated problems and be too reactive. Sometimes it's not so simple as just halogen order of reactivity. Am compensating for increased (or decreased) molar mass, but really would prefer to use the bromide. Maybe MEK instead of acetone? Don't have the phase transfer catalyst, but do have silica gel and some polyquat-7 I think. How about acetone/DMSO as the solvent system? Again, thanks to everyone for the help.

Globey - 4-4-2009 at 16:09

Quote: Originally posted by Arrhenius

In theory chloride to bromide wouldn't work very well. The reaction is entropically driven because sodium iodide is soluble in acetone, whereas sodium bromide (product) is not.

Typical procedure is to reflux in acetone with excess NaI, followed by aqueous workup.

[Edited on 4-4-2009 by Arrhenius]

Wouldn't the halide react with the hydroxyl during aq. workup, or do I need a strong base to deprotenate? There is no acid or base involved (just Na/KI & acetone), so workup means just successively diluting out the excess iodide with several DI water washes?

Globey - 4-4-2009 at 16:27

Another question. Would it be OK to use a saturated brine of NaI in acetone? Worried that maybe by salting out the cinnamyl chloride, it won't dissolve so easily in the acetone, and that would hinder rxn? Was thinking of quick and dirty, having saturated acetone with even excess NaI at the bottom of the flask. It could help to make the boiling more even. If this sounds remiss, please someone shout. Thanks

DJF90 - 4-4-2009 at 17:17

Ok Globey, do you want the bromide or the iodide?? Here is information on the finkelstein reaction:

http://www.organic-chemistry.org/namedreactions/finkelstein-...

It clearly states that KCl and KBr are insoluble in acetone, and so this is no way to go if you want the bromide. However if you want the iodide you can get very good yeilds by using an excess of KI. Being an allylic chloride, cinnamyl chloride is a very good substrate for an Sn2 reaction which this is, and the acetone will aid the Sn2 reaction as it is a polar aprotic solvent, meaning that the iodide ion is unsolvated and thus very reactive.

I would use a 1.5 molar equilvalent of KI and enough acetone to just dissolve everything. Make the solutions of the KI and the cinnamyl chloride separately and then add them together, and reflux with heat. I would leave the reaction for about an hour, and precipitate of KCl will be a rough guide to reaction progress. If in doubt follow the reaction with TLC.

For workup I would filter out the KCl, then distill out most of the acetone. This is to facilitate solvent extraction as acetone is miscible with water and orther common organic solvents, meaning that you wont get two phases when you try extraction. Add Water and a suitable solvent (perhaps DCM?) and this should take the excess KI into the aqueous layer and your cinnamyl iodide into the organic layer. Separate out the aqueous layer and wash the organic layer with perhaps a dilute thiosulfate solution and then a water wash. Finally dry over anhydrous magnesium sulfate or sodium carbonate (I would expect these to be suitable), filter, and then distill off the solvent.

Globey - 4-4-2009 at 19:40

Thanks DJF90. Realize KI will always be better, but is NaI fine on this one?

not_important - 4-4-2009 at 20:50

Compare the solubility of KI and NaI in organic solvents, the sodium salt is more soluble than the potassium salt in most common solvents ( Seidell's solubilities of inorganic and organic compounds is your friend, the 1919 2nd edition is available at the Internet Archives).

KBr is slightly soluble in acetone, but the ratio compared to KCl is fairly low, a clean reaction is doubtful and an excessive amount of acetone or alcohol would be needed.

When I performed this, after filtering out the NaCl, I would concentrate it until crystals started forming, then add several volumes of toluene or xylene and filter out the NaI precipitated, followed by a small quick ice water wash and drying with MgSO4.

Globey - 4-4-2009 at 21:01

not_important, perfect...am now prepared. My intuition would have told me KI the more soluble, so M=many tnx

DJF90 - 4-4-2009 at 21:44

Sorry, I knew NaI is more soluble but suggested KI because of the link I posted. Either salt should work fine but NaI is preferable due to its higher solubility in acetone.

Nicodem - 5-4-2009 at 01:42

Cinnamyl chloride is an allyl halide and as such it is highly electrophilic. Transforming it into cinnamyl bromide does not make much sense since there practicaly are no polar reactions where such a change would be considered rational (except for alkylations of carboanions at -78°C and similar low energy conditions). This is not like the difference in electrophilicity between alkyl chlorides and alkyl bromides, allyl and benzyl halides do not have such large gaps in reactivities.

The solubility of alkali salts in acetone (as well as in ethers) follows some simple rules to some extent: the more acidic the cation the more soluble the salt, also higher polarizability or hydrophobicity of the anion also immensily helps in increasing the solubility. Hence if you want to dissolve a chloride, you need an acidic cation like Li+. However, with such a large cation as the Cs+ things get more complicated, because even though this cation is essentially nonacidic its salts are nevertheless generally more soluble in organic solvents than potassium salts.
Anyway, since the chloride/bromide exchange with iodide in acetone does not follow SN2 rules of reactivities (Cl- in acetone is actually even slightly more nucleophilic than I-!), but is instead driven by solubility differences, it can not be efficiently used for alkyl chloride to alkyl bromide echange.

Globey - 5-4-2009 at 10:19

Nicodem,

Let me see if I follow. If it were between benzyl bromide vs/ benzyl chloride, then YES, it might make a difference, but the double bond (- wd'ing) here increases reactivity, so under normal alkylation conditions to typical substrates (OH in this case), cinnamyl chloride/bromide should pretty much be interchangeable? The end result will be a cinnamyl ether, with the rxn taking place in acetone/potassium carbonate at reflux. Many thanks

Ebao-lu - 5-4-2009 at 22:58

I am afraid, there can be a side reaction of alkylation of acetone because alcoholates are enough basic to form some equilibrium amount of acetonyl anion. But if is a literature procedure, then its fine.

[Edited on 6-4-2009 by Ebao-lu]

Nicodem - 5-4-2009 at 23:14

Quote: Originally posted by Globey

Nicodem,
Let me see if I follow. If it were between benzyl bromide vs/ benzyl chloride, then YES, it might make a difference, but the double bond (- wd'ing) here increases reactivity, so under normal alkylation conditions to typical substrates (OH in this case), cinnamyl chloride/bromide should pretty much be interchangeable? The end result will be a cinnamyl ether, with the rxn taking place in acetone/potassium carbonate at reflux. Many thanks

Not exactly. I said in my previous post that the reactivity difference between benzyl chlorides/bromides (like BnCl vs. BnBr), as well as between allyl chlorides/bromides (like in your case, PhCH=CHCH2Cl vs. PhCH=CHCH2Br) is no such big deal as with the difference between the reactivity of alkyl chloride/bromide reagents (such as, for example butyl chloride/bromid pair). Anyway, the point was the same - you can use cinnamyl chloride and get the same results, just follow the reaction progress.
Actually, even with alkyl chlorides it is often worthless to first transform them into alkyl iodides or bromides if they are primary and to be used in SN2 reactions. For example, if you would want to alkylate a phenol with butyl chloride it would not be rational to first transform it into butyl iodide even though this is much more reactive. A comparable yield can be attained by simply changing the reaction conditions, for example increasing the reaction temperature and using DMF as solvent, and eventually Cs2CO3 instead of K2CO3. Things are different if you have secondary alkyl halides which are already quite unreactive by themselves, then if you have a chloride instead of a iodide or tosylate, you are in troubles.

Also, as you were warned above, you can not use acetone if you are alkylating alkoxides. This type of reaction, the Williamson ether synthesis, is done in the solution of the parent alcohol.

Globey - 6-4-2009 at 16:57

Thank you all for the help...without it, I surely would be lost.