Example 1of US patent 3,932,384 awarded to Sawa et al. reads:
“The resulting crude base (17.4 g) is passed through a column of 87 g of silica gel and eluted with benzene to yield the pure base (15.58 g) which on recrystallisation from an azeotropic mix of benzene/n-hexane affords 15.64 g (93.2%) of 6-benzyl-3,4-dimethoxy-10,11-methylenedioxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine….”#
# There must be some error in their yield calculation
In 2009, when I searched, this was the only recorded example of recrystallisation from an azeotrope, with the exceptions of those using the commercially available azeotropes between water and ethanol, hydrogen chloride, or hydrogen bromide.
In a previous blog article, {https://kilomentor.blogspot.com/search?q=azeotropes#google_vignette}, KiloMentor proposed six azeotropes that might usefully serve as recrystallising solvents. Here, I want to look at a broader combination of common solvent possibilities.
In a binary lower-boiling azeotrope, each component of the solvent mixture reduces the cohesion of the molecules of the other component. As a result, the vapour pressure of the azeotropic mixture is greater than the sum of the partial vapour pressures of the components added together. Each component is repelling the other into the vapour above the mixed liquid itself. Consequently, the combined vapour pressures match atmospheric pressure at a lower temperature than either component boils separately.
If a binary mixture of solvents with the composition of a lower-boiling azeotrope were used to dissolve a practical amount of an essentially nonvolatile solute, such as would be required in a recrystallisation, and the mixture refluxed, the azeotropic mix of solvents might not distil over. The azeotrope might ‘break’.
The nonvolatile solute is likely, to some extent, to disrupt the original vapour-liquid equilibrium (VLE). A soluble solute almost always alters the relative volatilities of the two original components differently due to varying intermolecular interactions, which cause the composition of the vapour to no longer be identical to that of the liquid at the original azeotropic point. There is an uncertainty in using an azeotrope versus a single pure solvent for a crystallisation.
Indeed, some nonvolatile solute will cause the relative volatility between the two original components to become so large that the azeotrope disappears from the phase diagram. This turns the dissolving fluid into a simple mixture of the two solvents so that boiling will eject the more volatile of the two preferentially.
The addition of a solute sometimes can break an azeotrope if that solute interacts with and depresses the vapour pressure of one solvent component more than the other. A mixture of a solute dissolved in an excess of a lower boiling azeotropic composition cannot be concentrated without risking a change in solvent composition.
Indeed, the combination of a practical amount of a solute with a practical amount of a lower-boiling binary azeotropic mixture of solvents may cause phase separation if the solute there is enough solute and if it has a sufficiently overwhelming preference for interacting with one of the solvent components. Although phase separation may not occur when hot, the solute may oil out in a phase with one of the azeotrope’s components upon cooling.
Despite these unfavourable possibilities, one may be able to predict situations when a substrate has a structure that is likely to interact advantageously with a low-boiling azeotropic mixture of solvents during recrystallisation. A compound that has one portion of its structure that is preferentially solvated by one component of the azeotrope and another domain preferentially solvated by the second component is unlikely to break the azeotrope or cause phase separation. Furthermore, by the same reasoning, such a compound is likely to be more soluble in that solvent mixture than in either of its components alone.
Because a greater weight per volume of an amphiphilic substrate should be soluble in a lower-boiling azeotrope than in the same volume of either of its pure components, a better recovery of crystalline solute might be expected upon strongly cooling it.
Many potential solutes have apolar and polar/hydrophilic and hydrophilic domains within their complete structure, and it is these that are more likely to be usefully recrystallised from lower-boiling binary azeotropic mixtures of common organic solvents such as those below.
Azeotropic Solvent Mixture b.p.
5% ethanol in dichloromethane 39.0
7% methanol in dichloromethane 37.8
3% methanol in MTBE 52.6
31% water in MTBE 51.3
33% cyclohexane in acetone 53.0
41% hexane in acetone 49.8
12% methanol in acetone 55.7
7% ethanol in chloroform 59.4
13% methanol in chloroform 53.5
31% THF in methanol 60.7
20% isopropanol in methanol 64.0
46% hexane in THF 63.0
3% 1-butanol in hexane 67.0
4% allyl alcohol in hexane 65.7
22% 2-propanol in hexane 61.0
21% ethanol in hexane 58.7
23% isopropyl alcohol in ethyl acetate 74.8
31% ethanol in ethyl acetate 71.8
49% methanol in ethyl acetate 62.1
28% toluene in ethanol 76.7
30% isopropanol in 2-butanone 77.3
34% ethanol in 2-butanone 74.8
33% 2-propanol in cyclohexane 68.6
2% acetic acid in cyclohexane 79.7
31% ethanol in cyclohexane 64.9
33% 2-propanol in cyclohexane 68.6
42% toluene in isopropanol 80.6
12% water in isopropanol 80.4
28% acetic acid in toluene 105.4
Another way of looking at this is that these binary mixtures may be particularly good choices for mixed solvent crystallisations, no matter what the proportions.
Finally, some binary azeotropes show particularly large deviations from ideal behaviour. That is, their mixtures show the largest boiling point depression. These, quite possibly, can dissolve significantly more of an amphiphilic solute and give a higher recovery on cooling than other choices.
Selected Azeotropes with Big Bp Depressions
!st Solvent (bp) 2nd Solvent (bp) Az. bp. Dep.
Cyclohexane(81) Isopropanol (82) [67] 14
Cyclohexane (81) Ethanol (78) [65] 13
1-Chlorobutane( 78) Ethanol (78) [66] 12
2-Chlorobutane(69) Methanol (65) [53] 12
Ethanol (78) Hexane (69) [59] 10
Hexane (69) Isopropanol (82) [61] 8
Chloroform (61) Methanol (65) [54] 7
Hexane(69) Nitromethane (101) [62] 7
Acetonitrile (82) Isopropylether (67) [62] 5
t-Butanol (83) Hexane (69) [64] 5
1,2-Dichloroethane(83) Methanol (65) [60] 5
Hexane (69) 2-Butanone (80) [64] 5
Selection Criteria
- Greater than 10% of the minor component
- Azeotrope bp. <70 C
- 5 Cº degrees or more difference between the lower boiling component and the azeotrope
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