kilomentor

A significant factor in solvent choice for a process step is the problem separating the product from the solvent both grossly (as in filtering a solid away from a crysatallizing solvent, and more completely as in drying of solid moist with solvent. In the gross separation high boiling solvents tend to be more viscous than lower boiling solvents and filtration is slowed by increasing viscosity. In the drying step higher molecular weight solvents are generally harder to remove by evaporation.

Solvent displacement of tetramethylene sulfone

No azeotropes appear to be available for tetramethylene sulfone b.p. 130 C@ 6.5 mm. This solvent is reported to be particularly useful for dissolving aromatics for nitration, for alkylating tertiary amines and for displacement reactions using fluoride. The solvent is miscible with water and this could serve as a means of working up chemical reactions.

Suppose, at the completion of a reaction in tetramethylene sulfone we add an equal volume of a non-aromatic solvent such as isopropyl acetate or other semipolar solvent desirable for further processing and then slowly add the minimum amount of water required to cause the separation of phases such that the upper phase approximates the volume of the non water miscible solvent (isopropyl acetate). We could then separate the lower phase and extract with a second portion of isopropyl acetate to remove completely organic substrates into the upper phase.

One can then distil the tetramethylene sulfone-water mixture to drive off the water. The crude tetramethylene sulfone would be this way recovered for purification.

We could then combine the two extracts of isopropyl acetate and wash them with water thoroughly to remove the remaining traces of high boiling sulfone. The isopropyl acetate solution can be dried by azeotropic distillation. {The azeotrope has bp. 75.9 C producing two layers in a weight ratio of 88.9: 11.1 with the first upper layer constituting 98.2% isopropyl acetate and the lower aqueous layer containing 97.1% water. The relative proportions of upper to lower volumes are 91.4 to 8.6. The specific gravity of the upper layer is 0.870 and 0.995 for the lower phase.}

Using this method the mixture of water insoluble elements of the reaction mixture gets transferred to dry isopropyl acetate. This may or may not be an appropriate solvent for further processing.

For recrystallization, it is often useful to transfer the product mixture into a very polar or a very non-polar solvent. Isopropyl acetate enables both of these.

For a transfer to a more polar solvent, isopropyl acetate forms an azeotrope with methanol with bp. 64.0 C and composition 29.8 weight percent isopropyl acetate and 70.2 percent methanol. Thus in order to change solvent as efficiently as possible one needs to concentrate the isopropyl acetate solution as much as possible. This can be done under vacuum to reduce the heat that the product mixture is exposed to. This is likely to be important because the solution is going to evaporate on the walls of the containing vessel during the concentration leaving non-volatile product exposed to the heating required for the distillation. When the distillation has continued to the point that some product either begins to precipitate or oil out from solution or when the volume declines below the point of adequate stirring, whichever is the first to occur, then add methanol sufficient to give a weight ratio methanol to isopropyl acetate greater than 70.2%. Distillation under these conditions at atmospheric pressure will produce a distillate richer in isopropyl acetate than the pot mixture and will eventually lead to the complete removal of isopropyl acetate from the reactor. Depending upon the number of theoretical plates in the vessel /condenser assembly the distillate will be either the azeotropic composition or one richer in methanol. The poorer the rectification, the more methanol will be required to remove all the isopropyl acetate.

To switch to a very apolar system, going from isopropyl acetate, bp. 89 C to methylcyclohexane bp. 100.9 C or heptane bp. 98.4 C, one concentrates followed by fractional distillation of the more volatile isopropyl acetate. Because these saturated hydrocarbons have limited dissolving power for many functionalized substances, they are often good choices for recrystallization.

A more volatile replacement for isopropyl acetate like ethyl acetate or ethyl formate may be superior in an analogous procedure.

Piperylene Sulfone

While we are talking about the well known solvent, tetramethylene sulfone, it is worth mentioning the new “green” so-called smart solvent, piperylene sulfone. This is the addition product of the gas sulfur dioxide and the low boiling liquid 1,3-pentadiene. Piperylene sulfone is a liquid at room temperature (mp about 12 C) and can serve as a dipolar aprotic solvent quite like its cousin tetramethylene sulfone. The purported advantage is that it can be removed by thermal decomposition back into its volatile precursors and evaporation and then can be reconstituted for repeated use. There is plenty of discussion about piperylene sulfone out there. For more google piperylene sulfone.

Triethyleneglycol replacement by more common solvents

Triethyleneglycol is a polar, protic, high boiling solvent, which is fairly inexpensive. In the same way that tetramethylene sulfone is miscible with water and can be replaced (see above), so triethyleneglycol might be treated. The drying of triethyleneglycol by simple distillation may be too difficult however. Perhaps the drying could be done more easily as an azeotrope with toluene, for example, followed by driving off the excess toluene which will have less dipolar attraction to the triethylene glycol.

To transfer solutes from triethylene glycol solution to lower boiling water miscible solvents like ethanol or methanol the same two stage type procedure is used going to isopropyl acetate and then the alcohol.

Solvent Replacement of Quinoline

Quinoline is the solvent of choice in a number of reaction types where a high reaction temperature and a soluble base are both required. According to Fieser & Fieser’s Reagents for Organic Synthesis Vol.1, quinoline is used for the decarboxylation of unsaturated acids, because it is both basic enough to form the required carboxylate anion and because it boils at a temperature favourable for typical decarboxylations.

The solvent can also be useful for dehydrohalogenations where the product can in certain instances be distilled away from this solvent.

In cyclopropyl adducts with dihalocarbene simultaneous dehydrohalogenation and rearrangement can occur in boiling quinoline, sometimes even with distillation of the product as it is formed.

Quinoline may be an excellent replacement for pyridine, which has an offensive odor and is too water soluble for easy recovery

Quinoline is not soluble in cold water although it is soluble in hot. It is reported to be infinitely miscible with alcohol, ether, acetone , benzene and carbon disulfide. As a base it can form water soluble salts with acids. Quinolinium chloride is reported to be very soluble in water and the bisulfate is soluble in water and soluble hot in alcohol.

Even though quinoline is soluble hot in water, the products of a reaction in quinoline are unlikely to be separable from quinoline by extraction from a mixture of quinoline and water. The quinoline will co-extract into the organic solvent where it is more soluble. In a mixture of aqueous hydrochloric acid at pH 2-3 however one can expect to be readily extract neutral or acid reaction products into a water immiscible solvent leaving the quinoline as hydrochloride predominantly in the aqueous phase. Basifying this aqueous phase and cooling to about 0 C will separate a quinoline liquid for recovery. It will not be soluble in the aqueous brine, which has been formed by salt formation and subsequent neutralization. So long as the temperature is kept above –15 C the quinoline will not solidify. The organic extract should be multiply extracted with aqueous acid to remove the final traces of quinoline and these extracts can be discarded to the waste.

Propylene Carbonate

The substance is very soluble in each of water, alcohol, ether, acetone and soluble in benzene. The b.p. is 110 C @ 10 mm. pressure. The b.p. at atmospheric pressure is 240 C.

Although this solvent is very high boiling and can be used to displace low boiling solvents, it has the advantage that it can be hydrolyzed by aqueous acid to a polar water miscible component propylene glycol and the gas carbon dioxide. Propylene glycol moreover is not toxic.

A mixture of propylene glycol carbonate mixed with toluene for example could be hydrolyzed by sulphuric acid. As long as the main components of the reaction mixture were soluble in toluene and not in water, the propylene glycol would be hydrolyzed as it migrated partially into the aqueous acid, while the reaction products remained protected from the acid in the toluene. The mixture of propylene glycol and water could be separated from the toluene and the toluene re-extracted with water to remove the final traces of propylene glycol and propylene carbonate.

In using this approach it would be economical to concentrate the propylene carbonate solution as much as possible by distillation under vacuum before mixing it with the toluene and aqueous strong acid. In this hydrolysis the acid is only required in a catalytic quantity. It is not consumed in the hydrolysis.

Glycerin as a Reaction Solvent

Glycerin is non-toxic and miscible with water and alcohol. It is only slightly soluble in ether and immiscible with acetone, benzene, chloroform, carbon tetrachloride, and petroleum ether. Because it is probably immiscible with toluene (it is immiscible with benzene and pet. ether). Extraction of reaction components into this solvent will be possible. The extraction can be performed hot to facilitate separations by decreasing the viscosity of the glycerol phase. Glycerin is likely to dissolve many inorganic salts and it highly promotes hydrophobic associations such as those that promote Diels-Alder additions. The high temperatures possible may promote such additions. Rearrangements that require proton transfer can also expect to be facilitated in this solvent. The reaction of polar gases such as ammonia could be facilitated because the free ammonia would be solubilized by hydrogen bonding. This is an early example of a gas-expanded solvent, very topical these days.

Glycerin can be used as a chaser for any lower boiling solvent. Using some glycerine to provide fluidity and heat transfer properties any reaction mixture can be essentially taken to dryness by evaporation of all the solvent except glycerin. Addition of the new solvent and some water to dilute the glycerine allow the uptake into the new solvent. Washing with water completes the removal of glycerine. Traces of glycerine can be removed by adsorption onto many drying agents or on treatment with some periodic acid.

Ethylene Glycol as Solvent

Ethylene glycol has a high solvent power for sodium hydroxide and potassium hydroxide and the high boiling point permits raising the reaction temperature when desired. Ethylene glycol also serves as an efficient solvent for dehydrohalogenation.

Since ethylene glycol has the power to dissolve potassium fluoride it is the preferred solvent for the conversion of halides to fluorides.

In the Fischer indole synthesis a phenyl hydrazone of a ketone undergoes a tautomeric shift followed by sigmatropic rearrangement and elimination of ammonia to give indoles. The steps in this conversion are accelerated in ethylene glycol and even more so in diethylene glycol.

Diphenyl Ether as Solvent

Diphenyl ether forms an azeotrope with water, which boils just below diphenyl ether itself, at 121 C @10 mm pressure. The ether can be distilled down to reduced level and the remainder distilled as an azeotrope with glycerol.

If the diphenyl ether is diluted with hexane it can be extracted with methanol. Hexanes and methanol form two liquid phases. The goal here is to move the reaction reactants into the polar, low boiling alcohol phase and hold the phenyl ether as much as possible in the hexane layer.

Diphenyl ether can be used as a minor diluent in order to be able to evaporate to dryness so long as the temperature is maintained above 27 C the mp of phenyl ether.

Sulfonating the diphenyl ether, which should be very susceptible to such treatment, might work to remove the diphenyl ether into the aqueous phase. The sulfonation should be easily performed with ordinary sulfuric acid.

Diphenyl ether is often used for reactions that produce a salt product, which becomes insoluble in the solvent. In this situation the product can be isolated by filtration. In the synthesis of 4-hydroxy-6-methyl-2-oxo-1, 2-dihydro-pyridine-3-carboxylic acid ethyl ester in WO2003008414A1, the product is formed as a sodium salt of a beta diketo ester and this material is insoluble in the diphenyl ether so the solid is filtered off after diluting the reaction slurry with TBME. The solid was washed with TBME also. The mixture was acidified with conc. Hydrochlorid acid which allowed the product to dissolve and made residual quinoline dissolve as the hydrochloride in water. The product was extracted into chloroform.

A Possible Extractant for Dipolar Aprotic Solvents

A problem exists in process chemistry working up reactions done in an dipolar aprotic solvent such as DMF, DMA (dimethylacetamide), N-methylpyrollidone, etc. Most often one concludes these reactions by drowning out these solvents into a large excess of water and extracting the reaction products into some less polar volatile solvent, which is water immiscible. This method very substantially increases the total volume of the product mixture. In fact, this point in a process step most often becomes the point of maximum volume and this limits the amount of product, which can be produced from a single run in any particular size reactor. There is a need to develop some alternate method of isolation.

Work-Up of Dipolar Aprotic Solvents

To avoid the immense volumes that are obtained in the drown out procedures for these solvents using water, dilution with 2 or 3 parts can produce an aqueous mixture which can be extracted several times to quantitatively remove the reaction products without taking out too much of the dipolar aprotic solvent. These extracts because they are accumulated in a second vessel do not contribute to the point of maximum volume, enabling a larger charge in the reactor.

Then after the dipolar aprotic/aqueous phase is discarded, the combined apolar extract can be back extracted to remove whatever dipolar aprotic solvent that has been transferred.

• Chemical Blogs / Login
• Start Your Chemical Blog
• Chemical Forum
• Article Finder
• Periodic Table
• Chemical News
• Unit Converters
• pH Calculator
• Balance Chemical Equation
• Calculate Molecular Weight

• Main
• archives
• Albums
• Links

• Making a Good Recrystallization Process Step Better.
• Common Ground for Generic and Innovator Pharmaceutical Companies
• Biocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process Development
• Separation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.
• Sulfate Pharmaceutical Salts (reprint to remove comments)
• Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification
• Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.
• The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt
• Reiterating the Objective of the Kilomentor Blog
• The process vision: an integrating strategy in pharmaceutical process development
• Phosphate Pharmaceutical Salts : Chemical Process Development & Organic Synthesis
• Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperature
• Making the Hydrochloride Pharmaceutical Salt of Basic Drug Substances
• Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.
• Another Way to Separate Phenolics by Crystallizing of Co-crystals?

• General [62]

• RSS 0.90
• RSS 1.0
• RSS 2.0
• XML