How can this esterification be done? Experimental procedure please.
Thanks!solo - 23-8-2008 at 08:38
...............you must make the effort to find something yourself.....I just logged into google with your question and the answer is right
there....so no spoon feeding ......solo
........since I looked it up here is one bit of info,
Chloroacetic acid (MCA) & its sodium salt (SMA) may still be used as herbicides & may be available OTC. Sodium carbonate & sodium
hydroxide are OTC. Sodium cyanide, though, might get you a visit from the FBI. An alternate starting material would be either cyanoacetic acid or
sodium cyanoacetate.
An alternative to using ethanol & sulfuric acid in the last step is to react the disodium malonate with ethyl chloride in a solvent under
pressure. Ethyl chloride is sold as a skin cooling agent but it is Rx.
[Edited on 23-8-2008 by Ritter]
Sauron - 23-8-2008 at 08:57
This reaction is detailed exhaustively, with references, in Org.Syn.
In a moment I will post the pdf.
As Ritter says OS is upgefucked. The prep is however in CV 2 p.376.
It is also, in abbreviated form in Vogel's Preparative Organic Chemistry 3rd Edition which is in forum library. There'a a whole section on malonic
ester and acetoacetic acid syntheses.
Ritter gave the sequence properly but there's a lot of fine print you will want to know.
[Edited on 24-8-2008 by Sauron]Ritter - 23-8-2008 at 09:02
Quote:
Originally posted by Sauron
This reaction is detailed exhaustively, with references, in Org.Syn.
In a moment I will post the pdf.
The Org Syn site is having problems. I tried searching there earlier but some of the search functions are disabled.
Ludwig to the Rescue
Sauron - 24-8-2008 at 00:47
The prep from chloroacetic acid is described on pp 161-162 of Gattermann, attached below (from forum library.)
What the thread author asked was actually how to esterify malonic acid, not how to prepare it. The esterification is the last step before workup, and
as any tyro ought to know, is effected with an excess of anhydrous (absolute) ethanol and catalytic conc H2SO4.
Yes you're right Sauron. I need the experimental procedure of how to esterify malonic acid not how to prepare him! Because I wonder how the produced
water is driven off fom the reaction.
Thanks to you all...Sauron - 24-8-2008 at 09:52
You wonder how water is "driven off" in presence of concentrated H2SO4?
Think about it.
Then read Vogel's introduction to this chapters on aliphatic esters, dicarboxylic acids, and finally, malonic and acetoacetic acids.
You mix malonic acid with excess (3-4 mols per mol acid) absolute ethanol then you slowly add, with stirring, concentrated H2SO4.
Acids catalyze esterification. A little p-TsOH would also work, as would bubbling dry HCl gas through.
Now would you like to hazard a guess how you would recover malonic acid from its ester? Breaking up an ester into acid and alcohol is called
saponification. What sort of compound drives saponification do you reckon?
a. acid
b. base
c. Unobtainium nonachloride UnCl9
d. none of the above12AX7 - 24-8-2008 at 10:24
e. All of the above.
Incidentially, acid or base catalyzes cleaving an ester, base just works better. And why is another excellent question to be answered.
TimSauron - 24-8-2008 at 10:58
Here's Vogel p 483-485. Maybe clearer than Gattermann's verbage. Also he recites two different mechanisms, only one of which actually involves malonic
acid per se as an intermediate.
Not being much of a mechanic I do not recall which is now the preferred mechanism by contemporary lights.
AFAIK esterification of malonic acid is just a typical procedure akin to esterifying oxalic acid or succinic acid. That being said, I know that
malonic acid has some idiosyncratic properties. For example, while TCT readily forms oxalyl chloride from oxalic acid, HOOC-COOH, and siccinyl
chloride from succinic acid HOOC-(CH2)2-COOH, the reaction fails for malonic acid HOOC-CH2-COOH. Why? There does not seem to be any malonyl chloride.
(If there were, it would be a neat way to make diethyl malonate.)
Malonyl dichloride, the acyl chloride of malonic acid does exist. Aldrich sells it in 100 g ampules. Acros does not sell it. This is interesting.
There's a ref to Beilstein 2, IV. Was this only prepared in the second half of the 20th century? I will have to look this up. I wonder how they made
it. TCT failed, I would guess SOCl2 would also. PCl5 maybe? Why in ampules? Is it so air/moisture sensitive?
Introduction
I just finished a synthesis of diethyl malonate (DEM) using malonic acid in a Fisher esterification . I reported the synthesis of the acid in a
previous thread, "Oxidation of Diols."
DEM seems to be a very useful intermediate. For example, it can be used to make a carboxylic acid with 2 additional carbons starting with an alkyl
halide. My old organic lab manual (Brewster et al, 1962) uses it for making caproic acid.
Theory
CH2-(COOH)2 + 2C2H5OH ---- CH2-(COOC2H5)2 + 2H2O
The yield limit on most Fisher esterifications is about 67% due to equilibrium considerations. To increase this yield one of the reactants can be
used in large excess and/or one or more of the products can be removed during the rxn. Both of these techniques were used in the following synthesis.
Reference American Journal of Science, 1908, 4th series, Vol. XXVI, no. 153, Supplement: Art. XXV "On the Esterification of Malonic Acid," by IK Phelps
and EW Tillotson, Jr.
Specifically, the technique of Table II, C, 2, was used. In this case the authors reported a yield of 96.11%.
Procedure
a. reaction
15.4g malonic acid, 65 mL anhydrous ethanol, and 0.6mL conc H2SO4 were combined in a 250 mL RBF. This was placed in an oil bath in a simple
distillation set-up.
Along side that was placed a 500 mL RBF with 130 mL of anhydrous ethanol. This was used as a vaporizor, sparging ethanol vapor into the
esterification pot.
The oil bath was set at 105C. As the alcohol/water azeotrope was distilled off it was replaced with alcohol from the vaporizer. This removes water,
a product of the reversible reaction. This was continued until all the alcohol (65mL + 130 mL - that reacted) had distilled over.
b. workup
The 35 mL in the pot was placed in a sep funnel, chased out with a little DCM (I didn't have any ether). About 40 mL of sat aqueous Na2CO3 was added
until the mix was slightly basic. ~35 mL of DCM was then added to extract the DEM. The water layer was discarded. This was then washed with ~40 mL
of sat aqueous NaCl, discarding the aqueous layer.
c. vacuum distillation
The DCM/DEM extract was placed in a 100mL RBF for vacuum distillation. The oil bath was set at 60C then 70C until all the DCM and a little water had
distilled over. Vacuum was 16" Hg. Then the bath temp was raised to 140C and the DEM came over at 91-104C. Vacuum was 27.5" Hg.
Results
12 mL of DEM was produced for a yield of 53%.
Conclusions
Although the intended product was produced in reasonable purity, the yield is disappointing. I'm skeptical that the alcohol vaporization accomplished
anything. Increasing the batch size would no doubt improve yield by reducing mechanical losses. Ether might have been a better extraction solvent
than DCM.
[Edited on 15-10-2009 by Magpie]
[Edited on 15-10-2009 by Magpie]
[Edited on 15-10-2009 by Magpie]
[Edited on 15-10-2009 by Magpie]
[Edited on 15-10-2009 by Magpie]grind - 18-10-2009 at 14:05
Malonic acid + 5 moles of 95% ethanol + CHCl3 + a trace of TsOH at the Dean-Stark-Trap. Workup = only distillation, no need for washing, extracting
and so on. Yield should exceed 90%. Works excellently with oxalic acid (I produced diethyl oxalate in this way) with the only exception that no
catalyst is needed.Magpie - 18-10-2009 at 17:50
Good idea grind. I've never used a Dean-Stark system before. This looks like a justification for getting some equipment.
I don't have much chloroform. But I see in my handbook that benzene forms a low boiling ternary azeotrope with water+alcohol also. That I have.DJF90 - 19-10-2009 at 02:30
DCM also forms an azeotrope with water, although you need a dean stark for heavy entrainers. b.p. is about 38C IIRC.Jor - 19-10-2009 at 02:34
I think you can substitute the benzene for toluene.
Better for health, and nicer smelling.Arrhenius - 19-10-2009 at 06:29
Magpie: I think you may find that the amount of water produced in a Fischer Esterification reaction is rather negligible and need not be removed to
drive the reaction entropically. I wouldn't bother using a Dean Stark trap, which, by the way, won't work terribly well unless you use toluene or
benzene, which aren't an option as their BP's are above that of ethanol. Easier to use excess ethanol, ~2.2eq of H2SO4 and reflux for maybe an hour
or two. The 2 mole equivalents of water that are generated are not really sufficient to drive the reverse reaction. Think about it. If you want to
cleave an ester, you can use 1mole eq. of base, but usually use use an excess of water. As was mentioner earlier, acid hydrolysis of esters is also
slow. I think procedurally this would be easier. On another note, you might improve your yield by altering the workup. I would advise using
saturated NaHCO3 (saturated Na2CO3 is quite a strong base), and add the DCM or EtOAc to the crude reaction first, then wash with base, water, dry with
MgSO4 and evaporate. This way you avoid hydrolyzing any product. I should also think that the product obtained thereafter might be sufficiently pure,
making a vacuum distillation unnecessary.Magpie - 19-10-2009 at 08:21
Thanks for the reminder Jor. I always prefer to use cheap and readily available toluene in lieu of my precious benzene.
Arrhenius:
The bp of the benzene/ethanol/water azeotrope is 64.9C. So why wouldn't this work in the Dean Stark?
I see that you recommend 2.2 equivalents of H2SO4. Mimicking the old reference I cited above I used 0.14 eq H2SO4. I thought this seemed quite low
based on current practice for esterifications.
Thanks for the suggestions on a better workup. Arrhenius - 19-10-2009 at 14:55
If you form a Schiff base or something like this, and you use benzene or toluene, you'll collect a small amount of water in the DS trap, and you don't
really need to empty out your trap. You just run the reflux for a few hours. If you're azeotropically distilling and you're forced to remove the
azeotrope and cannot return it to the reaction (e.g. benzene/ethanol/water), then there's no sense using a DS trap. It may be possible to put
molecular sieves or some drying agent in the DS trap, but I've never actually done this. If you're going to empty the trap frequently you might as
well use a simple distillation setup as you have done already. Make sense? I only suggested 2.2eq of acid catalyst because this is typical for Fischer
Esterification, but I have not done so to make diethylmalonate.Magpie - 19-10-2009 at 15:48
Does water separate from the benzene/ethanol phase? If not I see where the Dean Stark would be of no advantage over simple distillation.
The authors of my reference in my 1st post did experiment with using 0.34 equivalents of H2SO4, but it showed no improvement over 0.14 equivalents.
Perhaps this is something specific to malonic acid. It is very vulnerable to decomposition, which in the end is one of the keys to its utility. not_important - 19-10-2009 at 19:47
Quote:
Does water separate from the benzene/ethanol phase? If not I see where the Dean Stark would be of no advantage over simple distillation.
See attached.
Quote:
The authors of my reference in my 1st post did experiment with using 0.34 equivalents of H2SO4, but it showed no improvement over 0.14 equivalents.
Perhaps this is something specific to malonic acid. It is very vulnerable to decomposition, which in the end is one of the keys to its utility.
I'm used to seeing fractional equivalents, too. The exception is when the H2SO4 is being used to tie up the water generated.
You can run an azeotropic system in an extractor, with a drying agent in the extraction section. This allows using less of the added azeotroping
agent, and can be handy when making medium sized batches of esters as you don't get the large volumes of distillate. Molecular sieves can be used; in
some cases MgSO4 or even Na2SO4 will work, especially if the extractor can be run so that the condensed liquids are cool to cold which increases the
stability of the hydrated salt.
Arrhenius - 19-10-2009 at 21:03
Which mol. sieves do you use with alcohol? Interesting table, I'll try to remember that.Magpie - 19-10-2009 at 21:14
Thank you for the information and data, not_important. Although not real efficient, it looks like using a Dean Stark would be worthwhile.
[Edited on 20-10-2009 by Magpie]not_important - 20-10-2009 at 00:24
3A sieves, 4A starts to pick up methanol and to a lesser degree ethanol.
Yes, the bz-EtOH-H20 azeotrope isn't a great one. Besides the ratios, the densities are close enough that droplets of the aqueous phase can get
carried over in the organic phase. But you just let it keep recycling and all the water eventually gets removed, once you get the input heat flux
right the setup requires little attention. tiger1 - 17-10-2011 at 06:46
Came across this thread via the SE with Malonyl Chloride. Per Sauron's idea I'm wondering if anyone has ever tried BzCl (Benzoyl Cl) to prepare the
Malonyl Chloride. BP of Malonyl Chloride is low at 53-55 so should distill out fairly easily and a small amount of base in pot would scavenge HCl. I
could almost envision after a small forerun of Malonyl Chloride, replacing the receiver with a flask of anhydrous ROH and if stirred, cooled, and N2
flushed, could simultaneously carry out the esterification. Feedback? Nicodem - 17-10-2011 at 07:27
The possible issue is likely to be the decarboxylation at the ClCOCH2COOH stage. This intermediate should decarboxylate at the temperatures required
for the unavoidable fractionation (55-100 °C). Since acid chlorination with acid chlorides is highly reversible you always have the sensitive
intermediate present all the time in the mixture in considerable amounts:
This is very much unlike in the irreversible chlorinations performed with SOCl2 or oxalyl chloride, where decarboxylation would not be much of an
issue. Since the reaction with BzCl relies on the removal of the lowest boiling acid chloride from the reaction equilibrium, the actual product is
likely to be either acetyl chloride or its mixture with malonyl chloride. In any case, the answer can only be found by doing a literature search or
experimentally.tiger1 - 20-10-2011 at 15:04
Thanks Nicodem, good point on unstable intermediate.DJF90 - 21-10-2011 at 04:24
If you have access to a dean stark trap, there is a paper utilising Fe2(SO4)3.xH2O as a catalyst for esterification, in toluene and alcohol leading to
almost quantitative yields in most cases. Two papers on the same subject, one for aromatic acids, the other for aliphatic.Boffis - 25-10-2011 at 09:27
@DJF90 do you have references for these two papers? They sound interesting on a general prep. level for estersDJF90 - 25-10-2011 at 16:36
Yes I do, but I'm on a mobile device at the moment. I'll post them in the morning if I remember, otherwise send me a U2U to remind me.
HOOC-CH2-COOH + 2 CH3-CH2-OH (with excess) --(traces of H2O, dehydrated CaCl2, HCl bubbles in solution, 70-80*C)--> Et-OOC-CH2-COO-Et ,
where the moisture is absorbed by CaCl2 while some gasos HCl dissolve in solution and protonates the alcohol to form the diethylmalonate ester.
now you have to heat the resulting compounds to 50*C for a while to allow remaining HCl and ethanol to escape from solution, then let the CaCl2 to
collect to the bottom and there you have it : pure diethylmalonate ester
If you use instead of HCl and CaCl2 , some H2SO4 ... you will have problems with separating the ester and with the conversion of ethanol to diethyl
ether during the reaction.AvBaeyer - 14-4-2014 at 18:06
Having looked carefully at the experimental sections for both of the papers cited by DFJ90 above, I find it hard to believe that the ferric sulfate is
doing anything for the reported esterification reactions in the absence of data for control reactions without ferric sulfate. The esterifications are
being driven by the removal of water, not by any ferric sulfate catalysis.
AvBMush - 7-6-2020 at 16:29
Mechanism of ferric sulphate catalysed esterification
Bioresource Technology 101 (2010) 7338–7343
Ferric sulphate catalysed esterification of free fatty acids in waste cooking oil
Alternative prep. methods
aluminum(III) sulfate, sulfuric acid, T= 100 °C
Kotake; Fujita; Rikagaku Kenkyusho Iho; vol. 1; p. 65
Personally I also doubt about the activity of Fe2(SO4)3 for esterficiation. Yes Fe +3 is a lewis acid but ... I don't know I does not 'feel' good.
The most important thing here is to remove water from the reaction to push the equilibrium to the ester buy removing continuously the water formed
along to "Lechatelier" Principle.
You can continuously remove water by azeotrope with i.e. toluene but for this reaction the problem is alcohol is also removed by azeotrope and has a
lower bp. This reaction use a catalytic amount of TsOH or better my favorite amberlyst-15 resin
The best option is to stay with H2SO4. Cheap and easy to get. Sulfuric acid is EXTREMELY dehydrating : less than 0.5 eq is way more than enough. If
too much is added it can kills malonate by inter-dehydrating it. I bet you can also do the reaction without heating thanks to the dehydrating power of
sulfuric acid. After a long reaction time, add water, extract with toluene of suitable solvent, combine the phases, washed the malonate with NaOH
solution,dry over MgSO4 then distill the toluene and the malonate. Its just an idea
Mush - 15-8-2020 at 13:37
aluminum(III) sulfate, sulfuric acid, T= 100 °C
Kotake; Fujita; Rikagaku Kenkyusho Iho; vol. 1; p. 65
Chemisches Zentralblatt; vol. 99; no. II; (1928); p. 1545
With hydrogen-chloride
Sugasawa; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; (1927); p. 150; Chemisches Zentralblatt; vol. 99; nb. I; (1928); p. 1643
With sulfuric acid
Sugasawa; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; (1927); p. 150; Chemisches Zentralblatt;
vol. 99; nb. I; (1928); p. 1643
With phosphoric acid
Lipp, Svetlana V.; Krasnykh, Eugenii L.; Verevkin, Sergey P.; Journal of Chemical and Engineering Data; vol. 56; nb. 4; (2011); p. 800 - 810
After a long reaction time, add water, extract with toluene of suitable solvent, combine the phases, washed the malonate with NaOH solution,dry over
MgSO4 then distill the toluene and the malonate.
I would expect sodium hydroxide to rapidly destroy the malonate ester, either by simple hydrolysis, or deprotonation of the central carbon.Dr.Bob - 18-8-2020 at 05:57
Washing with sodium hydroxide solution (or perhaps better sodium bicarbonate or carbonate) should not destroy much of the ester as long as it is a
wash for a few minutes, and not a long mixing. After the base wash, wash with brine to remove any remaining base. The basic hydrolysis of an
ester is best done with a water miscible organic solvent (not toluene) that will allow the base and ester to contact each other for a long time. So
merely washing with base in water, when using a hydrophobic solvent like toluene will not destroy much ester. The hydrolysis and even the
deprotonation of diethyl malonate take a long time in the correct solvent mixture.
