kilomentor | 09 April, 2007 19:29
The need for solvent exchanges
The need for solvent exchanges in the sense of displacing one solvent by another without passing through a liquid free state practically does not exist outside of process chemistry. At laboratory scale, when one solvent needs to be replaced with another, the solution contents are placed in a r.b. flask, set spinning on the vacuum rotary evaporator with appropriate heating and strong condensing efficiency. When the first solvent has been completely evaporated then the required new solvent is added and the solutes brought back into solution by swirling and scrapping.
On scale, evaporation to dryness is not possible without caking and possibly charring. Even if it were possible to avoid degradation, the layer of non-volatile residue would become so thick on the reactor's wall that heat transfer to complete the evaporation would be made impractically. Combined with this difficulty, at low volumes in a normal reactor stirring becomes ineffective. Thus solvent replacements must be done without completely removing the liquid phase at any point.
As an exercise let us consider solvent replacements among a dozen of the most common solvents. This examination is a logical analysis. None of the more complex multistage switches have been experimentally verified. The only inputs are known miscibilities, boiling points and the data from binary azeotrope tables.
The solvents are listed with their boiling points. I have named the list, Common Reaction Solvents, because they are not all solvents of choice for process chemistry. Chloroform for example would not be used today in a chemical process and hexane because of its flash point is questionable.
Methylene chloride 39.6
Ethyl acetate 77.1
There are 12 X 11= 132 possible binary replacements for this group of very common solvents. As we consider each of these challenges we will number the solutions with a number in brackets ( ).
So long as no azeotrope is formed any replacement from a lower boiling solvent to a higher one, so long as the difference in bps is about 30C degrees, it can be done trivially by simple distillation.
Thus methylene chloride can be directly replaced by ethyl acetate, ethanol, isopropanol, toluene, DMF or DMSO (6).
Acetone, chloroform, methanol, THF, hexane, and ethyl acetate can each be replaced by toluene, DMF or DMSO (18). Isopropanol can be replaced by DMF or DMSO (2) and toluene can be replaced by DMF or DMSO (2).Finally DMF can be replaced by DMSO (1).
We have just taken care of 29 of the 132 switches and have 103 left to consider. Obviously these are the least interesting replacements. The difficulty comes when chemists want to replace a less volatile solvent with a more volatile one on a scale where rotary evaporation is not possible. In fact, achieving this with dipolar aprotic solvents like DMF and DMSO is a frequent problem.
The most difficult replacements will those from a higher to a lower boiling solvent. Let us consider first the replacements from DMSO, the highest boiling solvent on our list.
When a replacement is done by simple single stage or azeotropic distillation one does not need to take into account the solubility of the non-volatile constituents of the solution. Whether these solutes are less soluble or more soluble in the second solvent compared with the first does not matter. Since solutes are relatively non-volatile they cannot escape. They stay with the liquid phase in the reactor no matter what it becomes.
Some exchanges cannot be performed by distillation alone but require at least one liquid-liquid extraction.
If DMSO is mixed with Mineral spirits (pet. Ether bp 179-210 C) and the mixture is distilled (preferably under high vacuum) DMSO, as the more volatile of the two liquids, will be displaced into the distillate leaving the non-volatile solutes in non-polar mineral spirits no matter what the solubility properties of the solutes are.
On the other hand, if DMSO is diluted with a little water and mixed with hexane, two phases can form, but the non-volatile solutes will only transfer substantially to the hexane layer if they are lipophilic.
Polar solutes will remain in the DMSO-water layer no matter that a choice of phases is available. Continuous extraction is not really a viable option at scale. In most cases, it is too complicated and too slow.
In solvent replacement schemes that comprise one extraction , the polarity of the solute being transferred is critical.
In this article I will use the term somewhat polar solute. The operational definition will be a solute that can in no more than three equal volume extractions be removed from hexane into methanol. Such solutes I imagine in my mind as being generally less than 400 Mw and contain several at least moderately polar functional groups such as alcohol, ketone, ester and amide.
Preparing a Methanol solution (M) of a solute
To transfer a somewhat polar solute from DMSO to methanol one can imagine the following sequence of steps:
1. Under vacuum concentrate the DMSO phase.
2. Add Mineral spirits
3. 3Co-distil to remove the last portion of DMSO
4. Add methanol to the mineral spirit/slurry or solution with the solutes
5. Stir the two phases.
Since Mineral spirits are mostly paraffin molecules, only the most apolar solutes will prefer that phase. Several extractions with methanol should transfer the solute. Wash the combined methanol extracts with hexane to remove traces of the high boiling Mineral spirits.(1) This solution in methanol will be called Solution M. It will beused as a starting point for other exchanges.
Alternately, if instead of Mineral spirits a liquid which is completely straight chain paraffins is used for the solvent being displacement, the residual paraffin can be removed from the methanol by recrystallizing urea from the methanol. This will generate urea inclusion complex, which will effectively remove the straight chain hydrocarbon from the methanol. Note that this idea has never been put to an experimental test. The formation of urea complexes with paraffins is treated in Differential thermal investigation of complex formation in the system urea-n-paraffin. A.V. Topchiev, L.M. Rozenberg, N.A. Nechitailo, E.M. Terent’eva, Zhurnal Neorganiicheskoi Khimii (1956) 1, 1185-93. and also the same authors Doklady Akademii Nauk SSSR (1954,) 98, 223-6. There is also an older article that touches on all the types of substances that can be treated this way, O. Redlich, C.M. Gable, A.K. Dunlop, R.W. Millar. Addition compounds of urea and organic substances. J. Am.Chem. Soc. (1950), 72, 4153-60.
Of course this option cannot be used, if the desired solute is a straight chain of more than 6 atoms with no significant branching. The solute would be trapped in the urea complex.
Using the Solution M just obtained above, the solute can be transferred to the headline solvents because every one of these forms an azeotrope with methanol. What is important in doing this is to concentrate the methanol solution to the smallest practical volume and then add sufficient of the second solvent to move to the correct side of the azeotropic composition so that one distils a vapour composition richer in methanol than in the second solvent causing the composition of the remaining liquid to become increasingly richer in the second solvent at the expense of methanol. (5) The acetone solution that is obtained by this exchange process is called Solution A and is used further below.
The Mineral spirits, which are like hexane probably, will form a clean two phase mixture with acetonitrile or acetonitrile with a trace of water and the somewhat polar solute will be transferred to this acetonitrile. Acetonitrile forms an azeotrope with ethanol and this sequence allows transfer from DMSO to ethanol.
The methanol solution which we have obtained above can be replacemented to toluene or DMF by simple distillation since there is a difference in bp of about 30 C. (2).
Transfer of a somewhat polar solute has already been achieved from DMSO to acetone in Section xx above. We still need to achieve transfers to methylene chloride, THF and IPA.
The replacement of a semi-polar solute with methylene chloride can theoretically be achieved by chasing the methanol with a polar solvent in which the semi polar solutes are insoluble.
Taking the methanol solution from Section X as a starting point, we can easily distil out the methanol replacing it with water. If the semi polar solute is insoluble it will separate as oil in water emulsion. When the entire methanol is gone, add methylene chloride to extract the solute, cut the phases and dry the methylene chloride by boiling out the azeotrope of methylene chloride and water.
A replacement to THF perhaps can be done starting with the solution in acetone from Section YY by addition of pentane to a mixture of acetone and THF. THF is not reported to form any azeotropes but pentane and acetone are reported to form an azeotrope of composition 21.0% acetone and 79.0% pentane which boils at just 32.o C and this is well below the bp of THF. This azeotrope therefore would be more than thirty degrees lower than the bp of THF. so they should easily separate. Once the azeotrope has been taken overhead, any excess pentane can be distilled away from the THF since they also still differ by about 30C degrees. Note that these schemes although logical conclusions from available data, have not been tested in the lab as far as I know.
The same pentane azeotrope trick should work even better for the replacement of acetone with Isopropanol. Addition of pentane and distillation of the acetone-pentane azeotrope followed by the remaining pentane should leave only isopropanol.
We have so far only considered replacementing a semipolar solute from DMSO. Suppose the solute is non-polar. If we blindly use our previous strategy which codistils first with Mineral spirits, the apolar solutes will remain in the Mineral spirits and not be extracted into either a methanol or an acetonitrile layer, so we are snookered.
In this situation we must rather displace the DMSO with a polar high boiling liquid. I would be worried to use a protic solvent like glycerine or diethylene glycol because the hydrogen bonding with the DMSO may create a maximum boiling azeotrope, which has not been documented or at least could raise the boiling point by entrainment of the DMSO. Triglyme or tetraglyme dimethyl ethers are liquids, which might be effective. Like DMSO they have no proton donors and they are sufficiently high boiling to allow selective volatilization of DMSO. Since they are miscible with water we can use the strategy of further decreasing the solubility in the glyme dimethyl ethers by diluting with water. Then we can expect to extract the hydrophobic solute into a low boiling medium like pentane. From pentane we can replace with any of the solvents from methylene chloride up to DMF (11).
If the solvent were are trying to use as our second solvent is higher boiling than methylene chloride we will have more flexibility and will choose something like hexane rather than pentane, which has too low a flash point for comfort in the plant.
An alternative to using a glyme methyl ether would be to use low molecular weight solid polyethyleneglycol. This material would chase the DMSO easily. It is really not volatile itself and serves just as a heat transfer medium while remaining liquid and stirrable in the reactor. When the DMSO has been driven off, addition of hexane or methyl t-butyl ether should precipitate the polymer and allow the solution of solute in the low boiler to be filtered away from the solid polymer.
This would depend upon the polymer not being soluble at all in the second solvents. Diethyl ether is the usual solvent used to precipitate polyethylene glycol, but it is not welcome in the plant setting.
The same strategies which we have applied with DMSO would be applicable to DMF and be easier to implement because DMF has a boiling point bout 30 degrees lower than DMSO but still very different from our other select common solvents. Again the intermediate solvent,which is used to chase the DMF can be either strongly hydrophobic or strongly hydrophilic to suit the solute.
With DMF another option which becomes more practical as the bp of the first solvent falls is steam distillation. Of course this choice is not made if the solute is appreciably water soluble.
An option that sometimes arises with solutes stable in strong acid is t hydrolyze the DMF after it has been concentrated to a high degree. The products dimethylamine and formic acid are both very water-soluble and are unlikely to solubilise most solutes.
In many cases where large volumes are not a concern, either DMSO or DMF can be diluted with a large amount of water and the mixed aqueous phase extracted with an immiscible organic phase. This of course cannot be done with very water-soluble solutes. It is however the most common work-up procedure and runs into trouble only on scale where high point of maximum volume limits the throughput. This is important in the early steps of longish processes.
Replacements from Toluene to Solvents of Lower Boiling Point
Isopropanol and toluene form an azeotrope bp 80.3 containing 5.0% IPA and 42.0% toluene. The two solvents also form a ternary azeotrope with water bp 76.3 which can be used to dry the IPA after the solvent replacement.
Ethanol also forms a useful azeotrope with toluene with bp 76.7C and composition 68% ethanol and 32% toluene. Again there is a ternary azeotrope with water bp 74.4C.
From ethanol one can replacement to ethyl acetate because there is an ethanol/ethyl acetate azeotrope bp 71.8 31.0%ethanol and69.0% ethyl acetate.
Methanol also forms a useful azeotrope with toluene with bp 63.7C and composition 72.4% methanol and 27.6% toluene.
Ethanol forms an azeotrope with hexane of bp 58.7C and composition 21.0%ethanol and 79.0% hexane
Chloroform forms an azeotrope with methanol BP 53.5C and composition 87% chloroform and 13% methanol.
To replacement from toluene to methylene chloride use the water azeotrope with toluene to remove all the toluene and give a water slurry, the extract back into methylene chloride after saturating the water with salt to increase the extraction efficiency.
The same method can be used to take the solute into the water miscible solvents THF and acetone. Once in water saturate the water with salt and extract. The saline will give two phases with either acetone or THF but this method is not clean and gives very wet solvents.
We have not achieved a good replacement between toluene and either acetone or THF. If we could find a replacement to acetone we could use the acetone/pentane method to get into THF.
Toluene can be taken into methanol and methanol into acetone; then acetone pentane can be removed from solution with THF to replacement to THF.
Replacements from Isopropanol to Lower Boiling Solvents
An azeotrope exists between IPA and EtOAc with bp 74.8 C and composition 77% ethyl acetate and 23% IPA.
An azeotrope exists between isopropanol and hexane with bp 61 C and composition 78% hexane and 22% IPA. Another azeotrope exists between Hexane and Ethanol with bp 58.7C and composition 21% ethanol and 79% hexane. Using these two azeotropes in sequence one can replacement from IPA to Ethanol.
The switches IPA to Hexane to Ethanol can be used.
The replacement from IPA to THF
IPA to Hexane; Hexane to Methanol; methanol to acetone; then mix acetone with pentane and THF and distil acetone/pentane azeotrope leaving THF.
The replacement of IPA with Methylene Chloride
IPA to water; water extract with methylene chloride
The Replacement of IPA with Chloroform
IPA to hexane; hexane to chloroform
Replacement from Ethanol to Ethyl Acetate
Ethanol to hexane; hexane to methanol; methanol to ethyl acetate
Replacement Ethanol to Hexane
Once a solvent change has been made to give a solvent with a bp of 60-70C there is no further incentive to change solvents. Solvents with a bp of 50-70C do not leave difficult to remove residuals when crystalline solids are separated from them either at atmospheric or reduced pressures. The reason for solvent replacements among solvents in this boiling rage is simply to find a solvent ffrom which the solute recrystallizes in a pure form, a high recovery and a desirable crystal morphology.
An acetone solution can by azeotropes replacement into bromopropane, acetone carbon tetrachloride, 1-chloropropane, cyclohexane, diethylamine, iodoethane, isopropyl ether, methyl acetate.
From chloroform one can replacement to methyl ethyl ketone.
From ethanol one can move to the solvents acetonitrile, benzene, carbon disulfide, carbon tetrachloride, 1-chlorobutane, chloroform, cyclohexane, dibromomethane,1,2-dichloroethane, diethyl formal (diethoxymethane), ethyl acetate, hexane, heptane, isopropyl acetate, isopropyl ether, methyl ethyl ketone, nitromethane, tetrachloroethylene, toluene, trichloroethylene, triethylamine.
Ethyl acetate ca be exchanged for the following pure solvents: carbon disulfide, carbon tetrachloride, ethyl acetate.
Hexane can be used to exchange for pure solvents: 1-butanol, t-butanol, isopropyl ether, methyl ethyl ether, t-butanol, nitromethane, n-propanol.
Isopropanol can lead to other pure solvents: cyclohexane, diisopropylamine, ethylene dichloride, methyl ethyl ketone, tetrachloroethylene, trichloroethylene.
Methanol can lead to pure solution through azeotropes: acetonitrile, benzene, cyclohexane, 1,1-dichloroethane, dimethoxymethane, dimethylformal, ethylenedichloride, ethyl formate, heptane, hexane,isopropyl acetate, methyl acetate, methylal, nitromethane, octane, trichloroethylene, trimethyl borate.Toluene can be used to provide pure solvents: acetic acid, t-amyl alcohol, 1-butanol, 1-chloro-2-propanol, epichlorohydrin, 2-ethoxyethanol, ethylenediamine, glycol, isobutyl alcohol, 2-methoxyethanol, nitroethane, nitromethane,1-propanol. pyridine.