After reading this primer on synthesis of carboxylic acids esters I came away with some questions...........
How much H2SO4 is added to a molar quantity of phenylalanine acid and how much alcohol, also will the ester rise to the top as an oil...or is there a
major work up to try to retrieve it? How long does one reflux the solution? and the temp is it just enough to get the alcohol to start bubbling?
....I just don't wish to go into this without some pointers......thanks for your interest...........solo
Note: I recently found this reference that might be of some interest....
The details depend on the particular ester of course... The amount of H2SO4 is relatively small (catalytic), as an example, I used 4 drops conc H2SO4
when esterfying 0.25 g salicylic acid and 1.30 g MeOH, although I did not try and optimize that amount.
More sulfuric presumably helps, as its dehydrating action will push the equilibrium forward.
Stochiometrically, acid and alcohol are in 1:1 molar ratio, but forward equilibrium is helped by using more of one of the components, whichever is
cheaper/more convenient.
Amount of heating varies, small esters are easy (i.e. hot water bath) but larger ones might need harsher conditions, you could also use azeotropic
removal of water to help things along, mol sieves to remove water may also help.Sauron - 19-8-2007 at 23:05
Since you are specifically asking about the esterification of an amino acid, I urge you to go to my posts in References regarding the pdf of THE
PRACTICE OF PEPTIDE SYNTHESIS which is the lab manual companion to PRINCIPLES OF PEPTIDE SYNTHESIS.
I made both available on 4shared.com, there is no password.DDTea - 20-8-2007 at 20:29
The reaction you are doing is a Fischer Esterification.
Some things I did when I did this reaction in my sophomore Organic Chem lab (I made Isoamyl Acetate, if I recall correctly) to promote high product
yields:
-Used a slight molar excess of Isoamyl alcohol
-Added silica gel as a desiccant to remove water formed during the reaction, thus driving the equilibrium to favor the products. Removing water is
essential in this reaction.
-We worked on a micro scale, so for a total volume of ~10 mL of reactants, we used ~1 mL 95% Sulfuric Acid as a catalyst
As far as heating goes, heat it such that it refluxes steadily, at which point hold it for as long as you'd like to let the reaction go (at least 1
hour). Once you decide it's done, you need to distill your ester to purify it--it should come over as an oil.
At least for simple esterifications, things work out this nicely. There may be special considerations for amino acids, as Sauron is suggesting.
I don't know what alcohol you are using, but tertiary alcohols may eliminate instead of esterify in this reaction.
Actually, once you finish refluxing your mixture, you will have to raise the pH such that the amino group on your ester is no longer protonated before
you can distill. That's the most obvious deviation from the simple esterification scheme I see.Klute - 21-8-2007 at 05:00
Depending on what alcohol your intend to use, a Dean Stark may be practical here. Toluene might work for ethanol, but it's not sure if the tertiary
azeotrope won't just send back "wet" EtOH in the reaction still... You may want to try lower boiling solvants as benzene (far from ideal - i
wouldn't work with it) or better cyclohexane. Check the azeotropes.
Also p-TsOH or other sulfonic acid might be more kind to the amino acid, while still being efficient catalysts.not_important - 21-8-2007 at 06:50
Simple hydrocarbons in the C6 to C8 range also work for azeotrope water removal. A pure, single isomer alkane means you'll see a simple azeotrope
coming over, but even a mixture such as light petroleum ether will function. This is assuming the smaller alcohols, up to C5 or so.
The alternative of using excess alcohol and 3A molecular sieves for water removal can work. Larger pore sieves, 4A and 13X, absorb smaller alcohols as
well. The sieves can be removed by filtering, stir sieves with fresh alcohol and filter to extract out the held-up reaction mix. The excess
alcohol is evaporated to recover the ester. Some drying agents start giving up absorbed water at temperatures in the range of the alcohol's boiling
point, sieves will not do so for the lower alcohols.
The amino-salt of a strong mineral acid, HCL or H2SO4, may be enough to catalyse the reaction, although 1% or so of the free acid might be needed.
That means you need enough acid to react with all the NH2 groups of the amino acid, plus a smidge.solo - 21-8-2007 at 07:58
So ...after reading the reference sauron alluded to , and reviewing the genenerous comments from the posters I should at least be
more complete about my experiment , as I'm trying to make a methy ester, using methanol and H2SO4..... the thought of using molecular sieves to
remove the water had not occured to me since the ester will float above the methanol, water and renmants of the H2SO4....I had just thought of
separating the ester and redestilling it to purify it ......however , I know need to rethink that strategy, as it will be put back in the kettle to
reflux in ethanol for 24 hours with 6NaBH4 to acquire the alcohol of the amino acid...phenylalaninol............solo
[Edited on 21-8-2007 by solo]Klute - 21-8-2007 at 17:40
I'm not sure the ester will seperate directly from the recation mixture, you might need to dilute with brine/water before that happens, and then
extact the aq. with a solvant.
MeOH will cause problems with a Dean Stark, to low boiling point... Using 3A Molecular seives as not_important suggested would be a alternative.
Is the methyl ester more reactive in the reduction? Because if using EtOH as solvant in the reduction, some transesterification might accur,
especially in anhydrous conditions.. In that case you might just aswell start with the ethyl ester.. It depends on the difference of these two
toward the hdyride and the extent of the transesterification..
WIll the NaBH4 reduce esters to alcohols alone? I thought you need some metal transition catalysts of some sort (Co2+, Ni2+..) but I don' remeber
correctly. I might be confusing with carboxylic acids.
Good luck with your reaction! Hope to hear about its advancesolo - 23-8-2007 at 07:29
It seems that the methods available ...one as Vogel* did preparing the ethyl ester using thionyl chloride or the "regular way", that is the using
absolute ethanol and dry Hcl.....and as suggested using 3A molecular sieves to prepare the absolute alcohol and also used during the reflux to take
care of any water produced .......as for the reduction of ester by 4NaBH4 it can be used by itself in ethanol even 50% and 50% H2O with yields in the
84% of the amino alcohol after 4.5 hours reflux ........solo
.....to a stirred , ice-cold suspension of (S)-phenylalanine(30gr. 0.182mol) in absolute ethanol (800ml.), thionyl chloride (32.5.gr. 0.273 mol) is
added dropwise, and the reaction mixture is then heated under reflux for 3.5 hours. The pale yellow solution is allowed to stand at room temperature
overnight, and then the ethanol is evaporated in vacuo to leave colourless crystals of the hydrochloride which are stirred with dry ether, filtered
off and dried in vacuo.
[Edited on 29-8-2007 by solo]Klute - 23-8-2007 at 17:04
Quote:
Originally posted by solo
.......as for the reduction of ester by 4NaBH4 it can be used by itself in ethanol even 50% and 50% H2O with yields in the 84% of the amino alcohol
after 4.5 hours reflux ........solo
Good to know.. is that from personal experience? Do you have a ref or tow to share?chemrox - 23-8-2007 at 23:58
sorry for a dumb question but why is too low a boiling point a problem for the Dean-Stark setup??solo - 24-8-2007 at 03:26
Quote:
Originally posted by Klute
Quote:
Originally posted by solo
.......as for the reduction of ester by 4NaBH4 it can be used by itself in ethanol even 50% and 50% H2O with yields in the 84% of the amino alcohol
after 4.5 hours reflux ........solo
Good to know.. is that from personal experience? Do you have a ref or tow to share?
---------------------------------------------------------------------------------------- Reference Information
Studies on Optically Active Amino Acids. V. Synthesis of Optically Active α-Aminoalcohols by the Reduction of α-Amino Acid Esters
with Sodium Borohydride Seki Hedeo 1 Koga Kenji 2 Matsuo Hisayuki 3 Ohki Sadao 4 Matsuo Ichiro 5 Yamada Shun-ichi 6 Chemical & pharmaceutical bulletin Vol.13, No.8, pp. 995-1000,1965
Abstract
A facile reduction of optically active α-amino acid esters and their hydrochlorides took place with sodium borohydride in ethanol or aqueous
ethanol to give the corresponding optically active α-aminoalcohols in fair yields. The reaction conditions were investigated.
Originally posted by chemrox
sorry for a dumb question but why is too low a boiling point a problem for the Dean-Stark setup??
Because you're trying to distill a water-containing azeotrope out of the reaction mix, removing the water to force the reaction. If one of the
materials boils without forming a water containing azeotrope, and boils much below the lowest boiling azeotrope, then you're not going to be removing
much water from the reaction mixture. No water removal - no forcing of the reaction to completion.
If one of the substances co-distills with water without forming an azeotrope, you can still go the Dean-Stark route. However if the condensed vapours
don't form at least two layer, one rich in water, you're going to need a lot more of the co-distillant to remove all the water than if you're able to
recycle it back into the reaction mix.Klute - 25-8-2007 at 16:16
Thanks Java for the ref!
For the Dean Stark, I had that kind of problem (co-distilling solvant) when doing aldol condensations, particuliary with MEk, which formed an layer on
top of the trap, sending alot of water back to the still (MEK can hold 24% of it'w weight in water). I had 3 layers, wet MEK, toluene, and a little
water at the bottom, but of course never arrived near the theoritical amount of water, and the using the Dean Stark became pointless, as high temp
caused higher condensation products.
But I'm drifting off subject here.WizardX - 26-8-2007 at 18:05
While catalytic reduction of benzylic type esters are achieve rather simply...
PhCH2OCOOR ==[H2/Pd]==> PhCH3 + HOCOOR ==> HOR + CO2
PhCH2OCONHR ==[H2/Pd]==> PhCH3 + HOCONHR ==> H2NR + CO2
Ref. Chem. Lett. Pg 1095 (Year 1976)
...the direct reduction of Phenylalanine ethyl ester to amphetamine is not so easily done.
However, I/we'll discuss further how this can be done when time permits me to type out the procedure.Sergei_Eisenstein - 28-8-2007 at 11:32
Browsing through the literature, I found a synthesis of amino acid ethyl esters that might interest you:
A Convenient Method of Preparing p-Toluenesulfonates of Ethyl Esters of Amino Acids Using Ethyl p-Toluenesulfonate
Kazuo Ueda
Bull Chem Soc Jpn 52 (1979) 1879-1880
Abstract - The treatment of amino acids with ethyl p-toluenesulfonate affords the p-toluenesulfonates of the ethyl esters in good
yields. Tryptophan ethyl-ester p-toluenesulfonate was also prepared in an 81% yield.
You can find experimental details in the paper. A preparation for ethyl tosylate can be found on Rhodium's site. Theoretically, you can also synthesize it from TsCl and EtOH.
[Edited on 28-8-2007 by Sergei_Eisenstein]solo - 29-8-2007 at 04:49
Method for extracting an amino acid ester from a hydrous solution of a mineral acid salt thereof Tomoko Kamashita, Hiroyuki Yamashita, Teruyuki Nagata, Masanobu Ajioka U.S. Patent #5374765
Abstract
Disclosed is a method for extracting an amino acid ester from hydrous solution which comprises adding thereto a water-soluble organic solvent and then
an amount of a base effective to liberate only a portion of the amino acid ester in the free base form into the organic layer, and repeating the
neutralization extraction steps until all of the amino acid ester has been extracted.
I have seen in Orgsyn about the reduction of esters to alcohols using Na/EtOH mixture, if needed I will find the reference again but my question is
can Lithium perform the same type of reaction? It seems to me that Sodium is used because it must be very fine and making sodium "sand" would be
simpler ten making the same with lithium since it floats on top exposing it to the elements.
Does anyone have references other then the orgsyn that I will provide if needed detailing the reduction of a carboxylic ester using Na/EtOH mixture?
