Sciencemadness Discussion Board - Failed alkaline de-esterification…

Failed alkaline de-esterification…

blogfast25 - 2-7-2011 at 06:08

I wanted to de-esterify isoamyl acetate to obtain isoamyl alcohol (banana oil) and went about it as follows.

78 g of isoamyl acetate, 45 g of KOH (10 % excess) and 40 ml of water were measured, combined and mixed, then refluxed at oil bath of 135 - 150 C for a full 2 hours.

The cooled organic phase was then separated by separation funnel, washed twice with KCl near saturated solution, then salted overnight with kitchen salt.

Trouble is: organic phase doesn’t appear to be isoamyl alcohol at all. Evidence:

- end ‘product’ smells exactly like isoamyl acetate, an unmistakable odour
- could find no K acetate in watery phase
- capillary BP determination gave a BP of 147 C, isoamyl alcohol is supposed to be 131,1 C, isoamyl acetate 142 C. Testing the source material also gave a BP of 147 C (where this discrepancy with the actual BP of isoamyl acetate comes from I do not know. Thermometer will now be checked against water).

I’ve done a few of these de-esterifications (methyl fatty acid esters, triglycerides, dioctyl phthalate) without problems, usually with much shorter reaction times.

What’s going on?

Edit: well, waddayaknow, both my thermocouples give a reading of 103 - 104 C for BP of DI water in the conditions used above. So that would put the BP of isoamyl acetate closer to the listed value. Must get a decent thermometer one day...

[Edited on 2-7-2011 by blogfast25]

Arthur Dent - 2-7-2011 at 07:45

Here's what I use:

Digital Thermometer - DealExtreme

It's surprisingly accurate, and it reacts quite fast, can be left on for a long time and uses very little battery juice.

I tried a few distillations and it does the job very well, and with DiW, you get precisely 100 deg. C.

That shop in China has some very interesting prices and shipping's free worldwide. On the down side, it's cheaply made chinese crap, but for the price, I can buy a few and it won't empty my pockets!

Robert

entropy51 - 2-7-2011 at 08:32

blogfast, I performed this reaction about 20 years ago, so I don't remember all the details.

I do recall that it required huge amounts of NaOH. I kept checking the aqueous layer and it was not basic so I added more NaOH. My recollection is that I did not heat it but stirred at ambient temperature for many days, adding NaOH all along.

When all was said and done I think that the yield was good. Hope this helps.

blogfast25 - 2-7-2011 at 10:01

Thanks Robert, that’s very good value for money and great temperature range too (up to 300 C!) I’ll be ordering tonight, methinks…

Entropy:

Interesting. There’s much more on the Net about acid catalysed esterifications than alkali based de-esterifications of course. Even with triglycerides you can use more or less the stoichiometric amount (see saponification number) and be done with (hot) in about a ½ hour. Wonder what makes this one so different. I’ll try a smaller batch with more alkali and less water…

There is of course one thing that makes actual saponifications somewhat different: the soaps actually phase separate, that's bound to pull the equilibrium to the right. Here the K acetate is supposed to stay in the watery phase.

[Edited on 2-7-2011 by blogfast25]

Nicodem - 2-7-2011 at 11:50

I have no experience with biphasic hydrolysis of esters, so I can't tell why it did not work. But I do have experience in monophasic ester hydrolysis and they work like a charm using 1-4 equivalents of NaOH or LiOH.H2O in methanol. You just let the reaction mixture stir for 24 h at room temperature. For most esters that's enough. Heating at 40-60 °C speeds up the reaction to be finished in a couple of hours for most esters.

Formates or trifluoroacetates will be gone in matter of seconds. On the other extreme, pivalates and t-alkyl esters might take forever at room temperature. However, acetates like yours should pose no problems.

I try to avoid systems where conversion depends on the minuscule solubility of a substrate in the aqueous phase (unless a PTC catalyst is used to drive the reaction in the organic phase). There are too much uncontrollable factors when kinetics rely on solubility. Though it might be just my prejudice - I'm an organic chemist so I want the reactions to proceed in the organic phase.

blogfast25 - 2-7-2011 at 11:57

Nicodem:

So, everything in one phase: a mixture of the ester, the alkali and the solvent (e.g. methanol), right? Sounds doable... I remember someone here carrying out the alkaline hydrolysis of DOP in IPA (Magpie, if memory serves me), then distill off the solvent. I'll try that... or be lazy and buy some 1-pentanol from abbey-chemical?

[Edited on 2-7-2011 by blogfast25]

Nicodem - 2-7-2011 at 12:15

Rather use methanol so that the reaction will truly be monophasic. NaOH or KOH is not equally well soluble in isopropanol and your ester will decrease solubility even further. The Na/K acetate precipitate might block the stirring, while in methanol it should stay in solution (unless too concentrated). Besides, check first for possible azeotropes with isopropanol. Even though you will have to fractionate the product in any case, if isoamyl alcohol for some reason forms an azeotrope with isopropanol, fractionation will be to no avail. For methanol, at least it is near to impossible to form an azeotrope with isoamyl alcohol and even if it does, a couple of aq. washes can remove it.

Just add your ester to a solution of 1.2 eq. NaOH or KOH in methanol (for example 2-3 times the volume of your ester, which should be enough to dissolve the hydroxide) and let it stir for 24 h. Then rotavap or distil off most of the methanol, wash the mixture with water and then brine, dry it over Na2SO4 or MgSO4 and fractionate.

UnintentionalChaos - 2-7-2011 at 12:23

I ran a large-scale prep of phthalic acid from vinyl glove plasticizers. I heated nearly to boiling with vigorous stirring to form an emulsion for 20 hours or so before the saponification was complete. Intimate contact between the phases is necessary and with the phthalates, the intermediate hemi-ester acts as a PTC. The significant amount of isopropanol in the mix probably also helped even though it was biphasic.

[Edited on 7-2-11 by UnintentionalChaos]

blogfast25 - 2-7-2011 at 12:45

Quote: Originally posted by Nicodem

Rather use methanol so that the reaction will truly be monophasic. NaOH or KOH is not equally well soluble in isopropanol and your ester will decrease solubility even further.

No, no, I wasn't suggesting to use IPA, just quoting someone else...

blogfast25 - 2-7-2011 at 12:47

Quote: Originally posted by UnintentionalChaos

I ran a large-scale prep of phthalic acid from vinyl glove plasticizers. I heated nearly to boiling with vigorous stirring to form an emulsion for 20 hours or so before the saponification was complete. Intimate contact between the phases is necessary and with the phthalates, the intermediate hemi-ester acts as a PTC. The significant amount of isopropanol in the mix probably also helped even though it was biphasic.

[Edited on 7-2-11 by UnintentionalChaos]

Yes, it was you and not Magpie.

kmno4 - 2-7-2011 at 14:12

I had the same problems with hydrolysis of ethyl acetate and buthyl acetate. With ethyl acetate, after prolongated heating, sudden reaction took place and mixure turn homogenous.
My patent for higher esters: use Ca(OH)2 [can be the shittest grade] and mix it with water and ester to get pasty mixture.
Nothing happens, but during ~30 minutes, mixture becomes warm and even very warm. It is good to stirr it (spoon) from time to time. When mixture is getting cold, hydrolysis is completed.

blogfast25 - 3-7-2011 at 11:48

Very interesting, kmno4.

Update:

84 g isoamyl acetate (i-amyl Ac), 31 g NaOH prills and 168 g of reagent MeOH were measured out and the latter two mixed.

The hot NaOH-MeOH solution was the added to the i-amyl Ac. Instantly the mass turned basically solid, with some generation of heat. Did the hydrolysis proceeds immediately this way?

The mixture was then further heated on an oil bath at about 100 C for an hour. Liquid could be seen to reflux:

To the still warm mixture, 100 ml of water was added and this dissolved the white crystalline mass very quickly and completely. A one phase system resulted and it didn’t smell like i-amyl Ac at all: more alcoholic, slightly oily, musty, reminiscent of IPA.

This solution was transferred to a clean distillation flask and over two and half hours distilled on an oil bath of 110 to about 140 towards the end. Distillate came over from 65 to about 80 C at the end, at a rate of about 1 drop per second.

Bottom fraction was about 179 g of a two phase system, the top presumably being the crude isoamyl alcohol, ready for work up tomorrow.

Nicodem - 3-7-2011 at 13:21

Good. Looks like it went OK. Don't forget to dry before the distillation or else you will first collect the water azeotrope.

The hydrolysis of most acetate esters under such conditions is rapid and the temperature increase by the exotherm increases the rate even further. But sodium acetate was probably just the minor component of the precipitate. At the very beginning, most of it was probably just sodium methoxide precipitating due to reduced solubility caused by dilution with isoamyl acetate. Over reaction time the composition of the precipitate changes to sodium acetate mostly.

Just a word of caution. You should never just pour reactants in the reaction mixture like that when doing a large scale reaction like this one, unless you checked the magnitude of the exotherm at a smaller scale experiment first (and even then, better not risk). This is a general warning, not meant to say that you did anything wrong in this particular situation, but that things could go seriously wrong in an even slightly different reaction. When performing large scale reactions, the reactants should be added in accordance to the monitoring of the temperature change.

Just guessing here, but weren't you interested in alcohols because you wanted to prepare alkyl bromides? If so, what is the purpose of first hydrolysing the ester? You can make the alkyl bromide directly from the ester under the same conditions like for alcohols.

blogfast25 - 4-7-2011 at 04:54

Nicodem:

I didn’t expect much by way of exotherm based on previous experiences and other considerations. The Na methoxide was added real slowly to avoid any surprises. The only surprise was the solid appearing. At the end of the completed addition the mass was just about hot enough to make MeOH boil lightly.

One-pot ester-to-haloalkane? Nope, I didn’t think of that. Acid catalysed decomposition of the ester, immediately followed by acid catalysed halogenation of the resulting alcohol? Interesting. It’s of course 3-methyl 1-bromobutane I’m after as alkylating agent for acetone, following in garage chemist’s footsteps.

As regards fractionating the product, do you think it’s really necessary, considering it will be brominated imminently? Washing with water, brine and subsequent drying over MgSO4, perhaps with a macro BP to characterise should suffice, no?

[Edited on 4-7-2011 by blogfast25]

Nicodem - 4-7-2011 at 09:39

Quote: Originally posted by blogfast25

One-pot ester-to-haloalkane? Nope, I didn’t think of that. Acid catalysed decomposition of the ester, immediately followed by acid catalysed halogenation of the resulting alcohol? Interesting.

Not necessarily an acid catalysed hydrolysis. Esters can also get protonated and thus undergo SN2 substitutions, just like alcohols. They are just much less basic than alcohols and therefore difficult to protonate. This is why methyl and n-alkyl esters can get cleaved with HI or Me3SiI even under anhydrous conditions where hydrolysis is not possible (HI/Me3SiI is an acid strong enough to protonate/silylate esters). So can do anhydrous HBr in acetic acid [1]. In the presence of water, which is about many thousand-times more basic than esters, the hydrolysis is probably more rapid than direct SN2.
At the end it does not matter goal-wise. I was just trying to point out that it is kind of obsolete to perform a hydrolysis when you don't actually need the isoamyl alcohol, but the isoamyl bromide instead.
Also, note that there are maybe just a few dozen examples of direct alkyl acetate to alkyl bromide transformations using HBr(aq) or HBr/H2SO4(aq) in the literature [2] (with good yields even on complex substrates), so for an amateur you can feel prouder than you would be performing something as trivial as an alcohol bromination. I saw no examples of NaBr/H2SO4 mixtures or similar being used, so it would formally be a new method as well.

[1] An interesting literature example is described in J. Org. Chem. 68 4499-4505 where a substrate containing secondary alkyl and primary alkyl acetate ester groups gets selectively brominated only at the primary alkyl group with anhydrous HBr in acetic acid. This is obviously indicative of SN2 mechanism.

[2] I'll point to just a couple of examples on simple esters:
J. Org. Chem. 14, 37–44: 87% yield on 5-chloroamyl acetate with HBr/H2SO4(aq)
J. Chem. Soc. 1962, 4286-4288: 71% yield on 5-acetoxy-4-methylpentanoic acid with HBr/H2SO4(aq)

Quote:

As regards fractionating the product, do you think it’s really necessary, considering it will be brominated imminently? Washing with water, brine and subsequent drying over MgSO4, perhaps with a macro BP to characterise should suffice, no?

If all you need it for is for the nucleophilic bromination, which is a pretty robust reaction in regard to impurities, than I would say you can surely skip the fractionation at this step. In any case, you will have to fractionate the isoamyl bromide, because starting the metalation with Mg is not as forgiving. So, you can postpone the purification for the next step.

blogfast25 - 5-7-2011 at 07:19

After washing several times with water, then twice with brine and drying overnight on anh. MgSO4 I’m getting a boiling point of about 131 C (with a revised capillary procedure - turned out my thermocouples were faultless but my procedure wasn’t - ouch!) So I’m pretty confident the product is at least technical isoamyl alcohol.

Further work up seems unnecessary, as you point out: the really needed work up will be on the 1-bromo-3-methylbutane, if I can synth it.

blogfast25 - 20-4-2013 at 05:18

Quote: Originally posted by Nicodem

Also, note that there are maybe just a few dozen examples of direct alkyl acetate to alkyl bromide transformations using HBr(aq) or HBr/H2SO4(aq) in the literature [2] (with good yields even on complex substrates), so for an amateur you can feel prouder than you would be performing something as trivial as an alcohol bromination. I saw no examples of NaBr/H2SO4 mixtures or similar being used, so it would formally be a new method as well.

Having blown my small stockpile of isoamyl alcohol on a failed alkoxide synth, I'll now have to consider doing this if I want to synth a t-alcohol from isoamyl acetate (using the isoamyl halide as an intermediate, of course) but definitely lack experience to even begin setting up a proposed procedure.

Firstly, I know the alkyl chlorides are not the best alkylating agents (in Grignard) but I don't have any HI or HBr. And KBr/H2SO4 tends to yield also Br₂, at least from what I've read. Perhaps H3PO4 could be used.

Isoamyl chloride has a BP (lit.) of about 100 C, so not ideal for further work up. But at least clean, conc. H2SO4 and NaCl I have!

And then there's all the rest. In terms of glassware I should have everything needed I think but what kind of recipe/methodology could be attempted? The abstracts provided don't really yield much to someone like me.

[Edited on 20-4-2013 by blogfast25]

Nicodem - 20-4-2013 at 07:22

Quote: Originally posted by blogfast25

Firstly, I know the alkyl chlorides are not the best alkylating agents (in Grignard) but I don't have any HI or HBr.

I think you misunderstand the formation of grignard reagents. You do not use the alkyl halide as alkylating reagents in Grignard additions. They are used to prepare the alkylmagnesium halides which then adds on the double bond of the ketone or other suitable electrophiles (in your case this is acetone). The alkylating ability of the alkyl halide therefore has nothing to with this reaction. Consider that even alkyl halides that are unable to act as alkylating reagents still do react with magnesium to form alkylmagnesium halides. On the other hand, primary alkyl sulfonates, which are generally excellent alkylating reagents, do not form the corresponding alkylmagnesiums under classic conditions. The mechanisms of electrophilic alkylation and formation of grignard reagents actually have nothing in common.

Quote:

And KBr/H2SO4 tends to yield also Br₂, at least from what I've read. Perhaps H3PO4 could be used.

Dozens of members used KBr, NaBr or NH₄Br with H₂SO₄ to brominate alcohols. The oxidation to bromine never was mentioned as a problem. I really cannot imagine how this could be a problem, if you consider the reaction conditions. It is the concentrated sulfuric acid that acts upon bromides by partially oxidizing them to bromine. Alcoholic and aqueous sulfuric acid does not significantly do that.

Quote:

Isoamyl chloride has a BP (lit.) of about 100 C, so not ideal for further work up. But at least clean, conc. H2SO4 and NaCl I have!

How are you going to use H₂SO₄ and NaCl to chlorinate isoamyl alcohol or its ester? What is the reference for this?

Quote:

In terms of glassware I should have everything needed I think but what kind of recipe/methodology could be attempted? The abstracts provided don't really yield much to someone like me.

I can give you the references, but I sure can't force you to read the articles.

blogfast25 - 20-4-2013 at 08:27

I expressed myself poorly there: I meant that the alkylating agent RMgX seems to form easier when X = Br or I, as opposed to Cl or F, from what I’ve read about it at least.

The articles themselves are behind paywalls, so I don’t have access.

It might also be simpler to synthesise a 2,2 dimethyl alkan-2-ol of sufficient chain length (4 to 6) by Grignard reaction of MeMgI with a butanoate, pentanoate or hexanoate ester of a short (to be disposed) primary alcohol. These esters are a little harder to find than acetates though. But all that belongs in the relevant thread.

Thanks for your help.

[Edited on 20-4-2013 by blogfast25]

Magpie - 20-4-2013 at 12:22

Quote: Originally posted by Nicodem

I thought I should add my recent experience as confirmation of what Nicodem is saying here. Wishing to prepare isopropyl bromide I first prepared 238mL of azeotropic HBr (47.6%) according to Brauer, p. 285. This was easily done using swimming pool grade NaBr and Rooto con H2SO4. This was then reacted with pharmacy grade 99% isopropanol according to Vogel, p.277 (yield isopropyl bromide = 51.3g; 42.2%).

So, I did this as a two-pot synthesis. If I'm reading this correctly Nicodem is saying that it can, and perhaps best, be done as a 1-pot synthesis.

Paddywhacker - 20-4-2013 at 19:11

Quote: Originally posted by blogfast25

...

The articles themselves are behind paywalls, so I don’t have access.

...

Having been there myself, I know how frustrating that can be.

Attachment: Brettle R, JCS, 1962, 4286-4288.pdf (308kB)
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Attachment: Cason et al., JOC, 1949, 14, 37-44.pdf (588kB)
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Attachment: Wang, Vina et al., JOC, 2003, 68, 4499-4505.pdf (157kB)
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blogfast25 - 21-4-2013 at 05:20

Thank you Paddywhacker. I've printed these off now and will scrutinise them for clues with regards to the synthesis of suitable bromo alkanes, directly from esters.