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Magpie
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[*] posted on 31-1-2010 at 14:01
ethyl n-butylmalonate failed synthesis


This synthesis, as described by OrgSyn in the link below, failed early for me. To 75 mL of absolute ethanol I had added 2.9g of Na which reacted to form the ethoxide without incident. However, immediately following the first drop of added diethyl malonate (DEM), a white precipitate formed. This is contrary to the OrgSyn description of a clear solution result.

The white precipitate was a very fine suspension, not filterable, which reminded me of a latex emulsion. Thinking it might be due to Ca++ contamination I tested the alcohol and sodium for Ca but the results were negative. When the DEM was added to the alcohol alone no precipitate formed.

Does anyone have any ideas why this anomaly occured, and/or any suggestions as to how I could determine the cause? I have no access to modern analytical instruments such as IR, etc. Any help would be much appreciated.

http://www.orgsyn.org/orgsyn/default.asp?formgroup=basenpe_f...

I couldn't get the complete link to post, so here is the pdf version:

http://www.orgsyn.org/orgsyn/pdfs/CV1P0250.pdf



[Edited on 31-1-2010 by Magpie]

[Edited on 31-1-2010 by Magpie]

[Edited on 31-1-2010 by Magpie]




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[*] posted on 31-1-2010 at 14:41


Uneducated guess(es):
The alcohol wasn't anhydrous and you saponified your ester with the resulting NaOH to sodium malonate?

Or maybe there was some acid impurity in the diethylmalonate which got precipitated as sodium malonate?

Or maybe orgsyn is wrong (unlikely).

Hard to say. Centrifuge it off and see what it is. :) Or just ignore it and accept the lower yields.
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[*] posted on 31-1-2010 at 15:25


I second Turds reply, the ethanol wasn't dry enough. The precipitate was sodium ethylmalonate. That's my best guess without being there.
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[*] posted on 31-1-2010 at 16:06


I disagree with the above comments. Obviously adding sodium to ethanol will yield an anhydrous solution of sodium ethoxide and a little bit of sodium hydroxide (soluble). NaOH will deprotonate diethylmalonate too. Also, sodium monoethyl malonate will probably be soluble as well (rarely do saponification reactions form a precipitate). I would guess that deprotonation will be many times faster than saponification. I would suggest you continue with the synthesis. Impure diethylmalonate is a more likely culprit. If you think it's the ethanol, add some sodium to dry it, and distill off the dry ethanol, then re-form the ethoxide and it should be free of sodium hydroxide.
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[*] posted on 31-1-2010 at 16:55


Quote: Originally posted by Arrhenius  
I would suggest you continue with the synthesis.


I have done this. To be exact, the procdeure I followed is a 1/2 scale version of that in Unitized Experiments in Organic Chemistry by Brewster et al. To summarize: after the addition of the DEM, 13.5mL of n-butyl bromide was added and the pot refluxed for 90 minutes. Then I attempted to filter off the white ppt. Whatman QA paper was a no go, even at the pump. I then centrifuged it for 10 minutes then filtered it by gravity. This removed the bulk of the ppt but the filtrate was still milky. The 50 mL of filtrate was distilled to remove about 40mL of ethanol. The remaining 10 ml was then washed with 50mL of water with 1.5mL of conc HCl added. This product was then washed with 20mL H2O and placed over ~1g of MgSO4. What is slowly forming on top of the ppt is an oil, about 3mL by now. This, I believe, is probably ethyl n-butylmalonate. Perhaps if I centrifuge the whole thing I can squeeze a couple more mL out of it.

In looking through my library I found the preparation of diethyl ethylmalonate on p.143 of the 1950 edition of Cummings, "Preparation 67." To confuse this situation some more, he says "The sodio-derivative of the ester is precipitated as a white solid." He then goes on to say that ethyl iodide is added as the alkylating agent. etc.

Edit:

My ethanol is Everclear (95% alcohol) dried over 3A molecular sieves. The DEM is homemade from 1, 3-propanediol as shown in "Prepublication" of this forum.

[Edited on 1-2-2010 by Magpie]




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[*] posted on 31-1-2010 at 17:46


Arrhenius,

*Obviously adding sodium to ethanol will yield an anhydrous solution of sodium ethoxide and a little bit of sodium hydroxide (soluble).
If it is too much water in the ethanol there will be a substantial amount of sodium hydroxide formed along with the ethoxide. The reason why the ethanol wasn't dry could be many (if that is the reason).

*NaOH will deprotonate diethylmalonate too.
In this case the hydroxide ion is a better nucleophile than a base.

*Also, sodium monoethyl malonate will probably be soluble as well (rarely do saponification reactions form a precipitate).
Saponification in such a relatively dry enviroment will, in my experience, almost always form a inslouble salt.

*I would guess that deprotonation will be many times faster than saponification.
Aboslutely! But if the reagent is a better nucleophile than base, as is the case of the hydroxide ion, saponification will win over deprotonation.

[Edited on 1-2-2010 by Barium]
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[*] posted on 31-1-2010 at 19:16


Well, we can agree to disagree. Strong base = strong nucleophile, basically (no pun intended). Though I don't generally think of hydroxide as a fabulous nucleophile (e.g. hydrolysis of an alkyl halide is slow). Recall also that sodium hydroxide in ethanol predominates as ethoxide, not hydroxide.

If the white precipitate doesn't disappear upon addition of the alkyl halide, it's probably not the sodium enolate of diethyl malonate (if you get what i mean). If you're having trouble filtering, try using celite. To avoid this, I would dissolve or suspend the crude product up in ethyl acetate and DCM and wash with bicarbonate, then dry and evaporate. Easy enough, right?
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[*] posted on 31-1-2010 at 19:34


If I add a solution of sodium hydroxide in ethanol to diethylmalonate, the ester will be hydrolyzed. If deprotonation occurs as one initial step, I don't know. But in the end there will be a sodium salt of malonic acid present.
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[*] posted on 31-1-2010 at 20:25


"...Strong base = strong nucleophile..."

Not necessarily. There are very strong bases that are essentially non-nucleophilic. This occurs due to steric hindrance about the center "bearing" the negative charge.

A large molecule, such as LDA (lithium diisopropyl amide), is the salt of a very weak acid (pKA ~36) and as such, is a ridiculously strong base. The bulky isopropyl groups prevent addition to an electrophile which nullifies the molecule as a classic nucleophile. This property allows LDA to be highly effective at pulling off most protons, viz creating enolates, whilst avoiding nucleophilic side rxns.

See also hindered base.

Cheers,

O3


[Edited on 1-2-2010 by Ozone]




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[*] posted on 1-2-2010 at 02:34


I'm sure Arrhenius knows this; LDA is a "standard reagent" in enolate chemistry. Conversely there are also comparably weak bases that are ridiculously (note spelling) good nucleophiles, for example thiolates.
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[*] posted on 1-2-2010 at 14:46


I centrifuged the product and decanted 2.8g of a clear oil with a smell of pineapple. This is a frustrating yield considering my charge of 20mL of hardwon diethyl malonate.

Gatterman (in the forum library) gives a procedure for making ethyl ethylmalonate. He calls the sodio ethylmalonate a "precipitate," as did Cumming.

Other than to purify my reagents, on which OrgSyn seems to put a lot of emphasis, I don't know where to go from here.




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biggrin.gif posted on 1-2-2010 at 21:31


Quote: Originally posted by Magpie  
What is slowly forming on top of the ppt is an oil, about 3mL by now. This, I believe, is probably ethyl n-butylmalonate. Perhaps if I centrifuge the whole thing I can squeeze a couple more mL out of it.


I'm a little confused about the workup procedure. Why do you have a precipitate at this point?

For starters, I highly suggest you restrict aqueous workups to a few simple solutions 1.) water 2.) 1N NaOH 3.) 1N HCl 4.) saturated NaHCO3 5.) saturated NaCl.

Here are possible contaminants which you'd like to remove in the workup:
-sodium hydroxide
-malonate salts
-ethanol
-alkyl halide

Don't bother removing the ethanol unless you have a LOT. I would pour the reaction into cold water (avoid hydrolysis) and extract into organic solvent (ethyl acetate is non-toxic, on top, and low bp). Then wash the organic phase with weak base (sat. NaHCO3) to remove free carboxylic acids, then water, then dilute HCl (to remove NaOH... though there won't really be any), then water, then brine... dry over MgSO4 and evaporate. Workup won't really get rid of alkyl halides, but it will remove everything else (except unreacted s.m.)

Start on a 1-3mmol scale (challenging sometimes) and you'll be less upset when things don't work (often).
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[*] posted on 2-2-2010 at 09:30


Quote: Originally posted by Arrhenius  
Quote: Originally posted by Magpie  
What is slowly forming on top of the ppt is an oil, about 3mL by now. This, I believe, is probably ethyl n-butylmalonate. Perhaps if I centrifuge the whole thing I can squeeze a couple more mL out of it.


I'm a little confused about the workup procedure. Why do you have a precipitate at this point?

For starters, I highly suggest you restrict aqueous workups to a few simple solutions 1.) water 2.) 1N NaOH 3.) 1N HCl 4.) saturated NaHCO3 5.) saturated NaCl.

Don't bother removing the ethanol unless you have a LOT.


Thanks, Arrhenius for your suggestions.

I can see why you are confused about this. After all my centrifuging and filtering the filtrate was still milky. Yes some of this white ppt went right through the filter paper. And I did try celite also. It collected a lot of the ppt but the filtrate was still milky. So when I distilled the 50mL of filtrate, removing 40mL of ethanol, the 10mL of residue was again quite milky.

My workup was simple and followed Brewster: 1) a wash with water containing some HCl, and 2) a wash with water. That was it.

This last centrifugation was to remove the ppt and MgSO4 from the oil, the putative product.

This white precipitate was a major PTA and made the workup very difficult. I still would like to find the answer to why Brewster, Vogel, and OrgSyn implied the sodio malonic ester was clear whereas Cumming and Gatterman used the word "precipitate."




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[*] posted on 2-2-2010 at 11:35


My guess is the filtrate is a salt of the product and starting material. You should quench the reaction with water dilute acid as soon as it's complete - not filter/centrifuge first. I presume the reaction uses an excess of base (ethoxide) and stoichiometric alkyl bromide. Hence you can still be forming a salt of the product, which might precipitate judging by your observation of the starting material precipitating.

I've run several org syn preps, and things don't go as well as they state. That being said, I have not run a single Org Syn reacion on the scale that they report (because it'd be huge), and I suspect that has something to do with it. Intuitively a solution at the same concentration precipitating doesn't make much sense, but that's my guess... difference in scale. And you're right, Org Syn places lots of emphasis on reagent purity, whereas I often don't. Regardless, a precipitate can still react, and i think you've got the product, but are losing it in the workup.
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[*] posted on 4-7-2014 at 14:26
Preparation of Ethyl n-Butylmalonate of July 2, 2014


A. Introduction & Background
As documented above my first attempt at this synthesis was a failure. But I always meant to try it again so back in May 2014 I did. This also was a failure. I used the same procedure as before so this came as no big surprise.

I was using the 1960 procedure in Brewster’s lab manual. Again, dealing with the fine NaBr precipitate was the major hangup, as was the separation following the water wash. Determined to make this work, I carefully compared the Brewster procedure (0.05 scale) to those found in Vogel (0.3 scale) and OrgSyn (1 scale). It became apparent that there was a significant difference that spoke directly to the problems I was having. Neither Vogel nor OrgSyn called for a filtration to remove the NaBr. And then, I saw in Note 4 of OrgSyn what really pleased me. It specifically said that it was not practical to remove the NaBr and that in doing so the following separation would not work well! I don’t know how I missed this in my earlier reading of the OrgSyn procedure.

B. Procedure for 3rd Try
For my 3rd try I generally followed the Brewster procedure as that was the scale that I wanted. But where it seemed prudent I adapted parts of the OrgSyn procedure. The Brewster reagent quantities are as follows:

ethanol: 150 ml
sodium: 5.8g
diethyl malonate (DEM): 40 ml
n-butyl bromide: 27 ml

1. I paid very careful attention to preparing “super dry” (<100 ppm) ethanol, starting with Everclear (95% ethanol), drying with burnt lime (CaO) per Vogel, then distilling onto 3A mole sieves. I found it interesting that when the distillate fell onto the mole sieves I did not see the usual evolution of tiny air bubbles. I took this as a very good sign indicating that there was no water present to drive out the entrapped air.

I also paid close attention to the cleanliness and dryness of my glassware. A base bath (NaOH in hot denatured alcohol) produced sparkling glassware. It was then dried for a few hours in an oven set at 130°C.

2. I used a magnetic stirrer with an oval stir bar (thanks Dr. Bob). I also added 3 boiling stones per Brewster. This worked very well and I had no bumping.

3. I used purchased DEM. As recommended by OrgSyn I began a redistillation of this commercial DEM under vacuum (P=2 mmHg). I expected some low boiling components, but there were none. The bp popped right up to 69.5°C and held there. So I used it “as is.”

4. My n-butyl bromide was homemade. As it had a correct and very narrow (1°C) bp range upon distillation I felt it was of high purity.

5. Most importantly, I did not attempt to remove the NaBr ppt.

6. Instead of refluxing for 90 minutes I refluxed for 2 hours per OrgSyn then checked the pH using moist litmus paper and moist pHydrion paper. Both indicated a slight basic condition (pHydrion: 8). OrgSyn said to continue the reflux until the pH was neutral. So I refluxed for another ½ hour and then checked the pH again. This time the litmus paper was a faint blue but the pHydrion showed a neutral pH. So I stopped the reflux at this time.

Prep of ethyl n-butylmalonate.jpg - 1.2MB
Reactants under reflux

7. Following the removal of the ethanol by simple distillation Brewster said to add 100 ml of water then 3 ml of con HCl. Assuming that the HCl was to be added to compensate for the short reflux time in Brewster, I followed OrgSyn and added none.

Distilling off the ethanol.jpg - 1.2MB
Removal of the ethanol

Following the removal of the ethanol (145 ml) the product consisted of an opaque white paste. When I added the 100 ml of water and swirled the paste disappeared and 2 clear phases resulted. I placed this in a separatory funnel and shook thoroughly. A clean separation then quickly followed with very little crud at the interface. I assume that the reason the NaBr is important here is that it is “salting out” the organic phase, giving a clean separation. The organic layer was then placed in a flask over some anhydrous MgSO4 for drying. This crude product volume was about 55 ml.

C. Vacuum Distillation of the Crude Ethyl n-Butyl Malonate (ENBM)

Today I vacuum distilled the crude ENBM using a vacuum pump (Harbor Freight $100 special). This produces a vacuum of ~2mmHg. About 9 ml of forerun came over as light boiling material. The remainder came over at 90°C as expected from the Sigma-Aldrich nomograph (http://www.sigmaaldrich.com/chemistry/solvents/learning-cent...). The resulting product weighs 32.9g which indicates a 55.3% yield based on DEM.

vacuum distillation of ENBM.jpg - 93kB
Vacuum distillation

vacuum distillation of ENBM insulated.jpg - 1.4MB
Vacuum distillation – insulated

distillate temp of ENBM at P=2mmHg.jpg - 1MB
ENBM distillate temperature at reduced pressure

pressure at distillation of ENBM (2 mmHg).jpg - 92kB
Reduced pressure

D. Discussion
After all the hours I put into the first 2 tries today’s result was very satisfying. Although I used purchased DEM I am convinced that the key change was elimination of the NaBr filtration step. I see that in Brewster’s 4th edition he has eliminated this procedure altogether. That was probably wise as I don’t see how this synthesis can be done well in just two 3-hr lab periods. This is unfortunate, however, as I feel that it has great pedagogic value. It’s also fun and very interesting. Questions, comments, and suggestions are welcomed, as usual.

E. References
1. Unitized Experiments in Organic Chemistry, 1960, Brewster et al.
2. A Textbook of Practical Organic Chemistry, 3rd ed, Vogel, p. 485 (1956).
3. Ethyl n-Butylmalonate, OrgSyn, Coll. Vol 1, p. 250 (1941)




[Edited on 4-7-2014 by Magpie]




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[*] posted on 5-7-2014 at 05:59


Very nice write up and work.

Searching for this product I can only come up with "Diethyl n-butylmalonate (CAS 133-08-4)". Is this what was synthesised and if so what purpose in life does it serve?

What's the actual reaction mechanism (neither of the links in the OP work). I'm guessing (not being much of an OC) an electrophilic attack by n-butyl carbocation on the central C atom of the diethyl malonate, followed by a hydrogen leaving from that atom?

[Edited on 5-7-2014 by blogfast25]




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[*] posted on 5-7-2014 at 07:11


Nice work Magpie. Well done.

My casual attempt to synthesize this failed at the first hurdle. I could not get my ethanol dry enough.

Quote: Originally posted by blogfast25  
Very nice write up and work.

Searching for this product I can only come up with "Diethyl n-butylmalonate (CAS 133-08-4)". Is this what was synthesised and if so what purpose in life does it serve?



This compound is a precursor of "Oxyphenbutazone" - An anti-inflammatory drug.
http://en.wikipedia.org/wiki/Oxyphenbutazone

gsd
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[*] posted on 5-7-2014 at 09:34


Thanks blogfast25 and gsd, I appreciate your interest and comments.

Yes, this compound is commonly referred to as ethyl n-butylmalonate but it is more accurately diethyl n-butylmalonate.

I too am no expert in OC but I'll give you my interpretation of the mechanism. This synthesis is an archetype "enolate" reaction where a carbon-carbon bond is formed. The basis of the reaction is the acidity of the hydrogens attached to the carbon lying between the 2 carbonyl groups of the malonate. These are highly labile due to the electron withdrawing power of the carbonyl oxygens.

When the elemental sodium is added to the ethanol in step 1 sodium ethoxide is formed. This is very cool to observe as the sodium pieces swim energetically around in the ethanol.

In step 2 the diethyl malonate is added. The ethoxide ion is strongly basic and pulls off a labile hydrogen from the malonate. This results in the formation of a carbanion malonate with the negative charge located at that central carbon.

In step 3 the n-butyl bromide is added. The carbanion malonate (a nucleophile) then attacks the n-butyl bromide in an SN2 reaction resulting in the diethyl n-butyl malonate product (DNBM).

But the interesting chemistry goes on from there. This compound and its analogs are very useful for making carboxylic acids. The DNBM will add 2 carbons to the bromide alkyl group.

I plan to use my DNBM to make n-caproic acid, a 6 carbon carboxylic acid, in this manner. I will describe that mechanism when I report the results of that synthesis (hopefully).

I should point out that although this is typically called an "enolate reaction," it is actually the tautomer of that enolate that is attacking the bromide, ie, the carbanion.

[Edited on 5-7-2014 by Magpie]




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[*] posted on 5-7-2014 at 10:30


Thanks Magpie.

At the risk of sounding facetious I'd say that a proton was pulled off instead of:

"and pulls off a labile hydrogen from the malonate"

...because otherwise no carbanion can be left behind.

Seems to me that plain oxidation of n-hexanol would be a much easier route to n-caproic acid though. But not as challenging... ;)

[Edited on 5-7-2014 by blogfast25]




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