Leyla-Cann
Sögütoglu
,
René R. E.
Steendam
,
Hugo
Meekes
,
Elias
Vlieg
* and
Floris P. J. T.
Rutjes
*
Radboud University, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. E-mail: F. Rutjes@science.ru.nl; Fax: +31 24 365 3393; Tel: +31 24 365 3202
First published on 13th July 2015
Crystallisation processes have evolved to practical methods that allow isolation of an enantiopure product in high yield. Viedma ripening in particular enables access to enantiopure products in a reliable way, simply through grinding of crystals in a solution. This tutorial review covers the basic principles behind asymmetric crystallisation processes, with an emphasis on Viedma ripening, and shows that to date many novel organic molecules can be obtained in enantiopure solid form.
Key learning pointsSolid-state versus molecular chiralityAsymmetric crystallisation from solution Deracemisation through Viedma ripening Crystal growth Racemisation |
After its discovery in 2005, an increasing number of reports demonstrate the broad applicability of Viedma ripening which enabled the complete deracemisation of a large variety of crystalline chiral compounds.3 Section 2 of this tutorial review covers the basic principles behind asymmetric crystallisation processes with a brief history on the discovery of Viedma ripening. The principles underlying Viedma ripening are addressed in Section 3. Finally, a number of recent applications involving crystallisation-induced deracemisation methods are highlighted in Section 4.
Fig. 2 The formation of crystals from solution proceeds either through primary-(homogeneous or heterogeneous) or through secondary nucleation. |
In a simplified view, crystal growth encounters a barrier as a result of unfavourable crystal-solution surface energy versus favourable bulk energies. The critical nucleus size (r*) is reached when the favourable and unfavourable energy contributions just counterbalance. Note that the critical nucleus size for primary and secondary nucleation does not need to be the same as it depends on an interfacial energy contribution. Once an aggregate is larger than the critical nucleus it can grow ‘downhill’ spontaneously. In other words, the crystal as thermodynamic end product has a kinetic barrier called nucleation barrier. The barrier can be reduced by primary heterogeneous nucleation (red curve) or even ‘disregarded’ by using secondary nucleation (green area), which supplies clusters, usually larger than the critical nucleus.
For further reading on the crystallisation of molecules from solution, the reader is advised to consult a previously reported tutorial review.5
ee (%) = (([R] − [S])/([R] + [S])) × 100 | (1) |
In the solid state, chiral discrimination is easier to realise. This especially applies to molecules which, in the crystal structure, have a greater affinity for the same enantiomer than for the opposite enantiomer (Fig. 3). Such a racemic conglomerate is in fact a mechanical mixture of enantiomerically pure crystals of one enantiomer and its opposite. This is the case for approximately 5–10% of all chiral crystalline molecules.6 When molecules have a greater affinity for the opposite enantiomer than for the same enantiomer, the molecules form a single crystalline phase in which the two enantiomers are present in an ordered 1:1 ratio. The crystallographic unit cell contains both enantiomers and the solid is called a racemic compound or true racemate. Approximately 90–95% of all crystalline racemic mixtures form racemic compounds. Finally, in less than 1% of the cases a racemic mixture crystallises as a solid solution, containing molecules of each enantiomer in a random arrangement. A unit cell can still be assigned, but the molecular filling of this unit cell is not as well-defined as in the case of a true crystal.
Fig. 3 Enantiomers crystallise either as a racemic compound, racemic conglomerate or a solid solution. |
Fig. 4 Crystallisation of conglomerate-forming molecules in (a) the absence and (b) presence of solution-phase racemisation. |
To prevent the nucleation of the other enantiomer, Egbert Havinga used conglomerate-forming quaternary ammonium iodide (Fig. 4b) that racemises in solution as a spontaneous process toward maximal entropy.9,10 Because of the decrease in supersaturation due to the first crystal formed (Fig. 2), primary nucleation of either enantiomer will less likely take place. As the mother crystal grows larger, it retains its chirality by taking up only the monomers with matching chirality. The supply of these monomers is maintained through racemisation in solution. This way enantiopure crystals spontaneously form without the need for separation. This process is also known as total spontaneous resolution.6
Havinga postulated in 1941, at the Dutch organic chemistry conference, the three requirements for a racemic mixture to have a high probability to undergo total spontaneous resolution:9
(1) The compound must form separate R and S crystals (i.e. the compound is a racemic conglomerate).
(2) The compound must be able to racemise in solution, possibly aided by a catalyst speeding up the racemisation.
(3) The rate of crystal nucleation is low, while the rate of crystal growth is high. The rate of racemisation should be high as well.
At first Havinga was unaware of the impact of his research, which was published in the Chemisch Weekblad, a journal written in Dutch. Soon after a publication of a model on spontaneous asymmetric synthesis by the theoretical physicist Sir Charles Frank,11 Havinga published his experimental findings again, but this time in English in an international journal.10 Interestingly, an often overlooked detail in the experimental section of the Dutch paper is that Havinga mentions that in some experiments several crystals were formed as the result of agitation. When combined, the mixture of crystals still displayed optical activity. Havinga proposed that these crystals were grown from seeds originating from the initial mother crystal (secondary nucleation) and therefore were of the same handedness (Fig. 5).
Fig. 5 Primary nucleation to give an enantiopure crystal which can grow larger (top) or will undergo secondary nucleation (bottom). |
This effect of secondary nucleation was studied in 1990 in more detail by Kondepudi et al. who found that crystallisation from a stirred solution12 or melt13,14 leads to many small crystals which are nearly all of the same handedness. In their solution-phase experiments, the compound used was sodium chlorate which is achiral as a molecule in solution but in the solid state the arrangement is such that the crystals become chiral (Fig. 6).
Kondepudi et al. showed that nearly all crystals (99.7% of all crystals formed in an experiment) had the same chirality when an aqueous solution of sodium chlorate was stirred during crystallisation. He stated that “in order to produce total asymmetry of close to 100% in the product crystals in every try, autocatalysis and competition between the L- and D-crystals are needed.” In Kondepudi's experiment too, all requirements for total spontaneous resolution as stated by Havinga are met: (1) NaClO3 crystallises as chiral crystals (thus being a conglomerate in the solid state), (2) racemisation in solution is not even needed, because the building block is achiral and (3) the rate of primary nucleation was kept low, while the rate of crystal growth was high. The latter condition was possible, because Kondepudi made use of the rapid generation of secondary nuclei which reduced the concentration to a level at which the rate of primary nucleation is virtually zero under stirring conditions. Primary nucleation is a cumbersome process, with a kinetic barrier of reaching the critical nucleus, whereas secondary nuclei larger than the critical nucleus grow as soon as they are formed. As such, the left- and right-handed nuclei generated through secondary nucleation compete for the solute and the rapid crystal growth suppresses primary nucleation and therefore the formation of nuclei of the opposite handedness. In addition, Kondepudi noticed that when the solution is not stirred, there is no preference for one chiral form over the other. This means that all of the nuclei are produced through primary nucleation, homogeneous or heterogeneous, and their handedness is at random. In this case too, the depletion of the solute due to crystal growth may eventually stop the primary nucleation, but no chiral resolution occurred in these trials.
Later, Durand et al. showed that the asymmetry obtained through stirring-induced crystallisation of a conglomerate-forming achiral molecule can be converted to molecular chirality.15 Stirring during the crystallisation of conglomerate-forming molecules which racemise in solution provides an attractive route to obtain molecules in high ee and high yield.16 However, it is not the most reliable approach in reaching an enantiopure product as nucleation of the unwanted enantiomer still can take place.
Viedma discovered that the initially racemic mixture of sodium chlorate crystals was, over a period of several days, completely transformed into an end state in which all of the crystals were of one chiral form. This transformation, which is now called Viedma ripening, involves solid-to-solid deracemisation instead of solution-to-solid deracemisation and is therefore significantly different as compared to total spontaneous resolution.
Like Kondepudi et al., Viedma used the achiral molecule sodium chlorate in his experiments. In 2008, Noorduin et al. extended Viedma ripening to intrinsically chiral molecules.19 They showed that amino acid derivatives, such as the one depicted in Fig. 8, can also undergo solid-to-solid deracemisation. These molecules also form conglomerate crystals and undergo racemisation in solution using a strong base. Noorduin et al. showed that Viedma ripening of this compound can readily be scaled up to larger volumes of up to 320 mL of solvent, thereby demonstrating the industrial viability of Viedma ripening.20 In addition, other pharmaceutically-relevant molecules, such as Naproxen21 and a Clopidogrel intermediate,22 were found to undergo complete deracemisation through Viedma ripening. The final configuration of the product can easily be controlled using additives,19 difference in crystal size between the enantiomers23 and even the order of process steps.24
Fig. 8 Extension of Viedma ripening to intrinsically chiral molecules that form racemic conglomerate crystals. |
During the past decade, several research groups have studied the mechanism behind this intriguing transformation. Although “the practical execution of the process is remarkably simple”25 the underlying mechanism is more complicated. After symmetry breaking of the racemic mixture of crystals due to random local fluctuations in ee or local fluctuations in the crystal size distribution (CSD) difference between the enantiomers, the system undergoes complete solid state deracemisation through an autocatalytic feedback mechanism in which the initial ee is amplified exponentially to an enantiopure end state. To date, many computational studies have been carried out to explain the mechanism behind Viedma ripening. To account for all these models, however, is beyond the scope of this review. Still, most modeling studies describe the Viedma ripening process along the four factors described in the following paragraphs (also indicated with the numbers in Fig. 9).25
Fig. 9 Schematic representation of a proposed mechanism behind Viedma ripening. The numbers are explained in the main text. |
As the following section will show, novel applications involving Viedma ripening and total spontaneous resolution are still being discovered.
Another contribution to the discussion on the origin of single chirality was proposed by Frank, already in 1953. Frank envisaged that an enantiopure product can in principle be formed from achiral starting materials provided that the product enantiomer catalyses its own formation and at the same time suppresses the formation of the other enantiomer.11 He concluded his article with the sentence “a laboratory demonstration is not necessarily impossible”. It took nevertheless more than 40 years until Frank's concept of asymmetric autocatalysis was experimentally realised. Asakura et al. found that an optically active cobalt complex can be formed through asymmetric autocatalysis.31 In the same year, Soai et al. showed that an initial small amount of chiral product can be amplified to single chirality.32 Without the addition of enantioenriched material from the beginning, however, enantiopure products could not be obtained.33 These results underline the fact that the synthesis of an enantiopure product from achiral reactants without pre-existing enantioenrichment still is extremely difficult to achieve in solution. More recently, some of the present authors successfully extended Frank's concept to a synthetic organic construction reaction34 in which crystals of the product were used as the asymmetric autocatalytic driving force (Fig. 10).35
It was found that the product amine forms racemic conglomerate crystals while in solution it can racemise through a reversible aza-Michael reaction. Starting at a high concentration of achiral reactants, both enantiomers of the product are rapidly formed using DBU as an achiral catalyst in solution. Due to the poor solubility, both enantiomers of the product crystallise to give a crystal-solution system. The latter system subsequently undergoes deracemisation through Viedma ripening due to the applied grinding conditions. This way, an enantiopure product was reproducibly obtained in high yield from achiral reactants in a single reaction. The enantiopure product was formed either in the (R)- or (S)-configuration.
The reversible reaction can also be used to enhance the ee of other conglomerate-forming molecules, as was shown for a reversible Mannich reaction36 and a reversible aldol reaction.37 In addition to a reversible reaction, racemisation can also be induced in different ways as some recent reports have shown (Fig. 11). The group of Hakånsson significantly extended the list of metal complexes that can be resolved through total spontaneous resolution (Fig. 11a).38,39 These complexes have achiral ligands but are chiral (denoted Δ or Λ instead of R and S) as a complex. On the other hand, pyrimidine-derivatives studied by Yagishita et al. exhibit axial chirality and these molecules as such were found to undergo racemisation through an achiral transition state at elevated temperatures without the need for a catalyst (Fig. 11b).40 The combination of seeding and stirring gave the product with an ee of up to 91% through total spontaneous resolution. Another class of compounds that can be obtained in enantioenriched form through total spontaneous resolution are isoindolinones (Fig. 11c). These compounds undergo rapid racemisation through a ring-opened achiral intermediate in the presence of a strong base (DBU). Starting from a clear solution, evaporation of solvent led to the crystallisation of enantioenriched isoindolinones in quantitative yields through total spontaneous resolution.41 Some of the present authors later reported that the isoindolinones can be deracemised completely through Viedma ripening provided that (1) there is sufficient attrition, (2) a suitable solvent is used in which the compounds have a high enough solubility and (3) that racemization is avoided during the ee analysis.42 Moreover, the reported isoindolinones readily racemise in ethanol without a catalyst and this enabled the complete deracemisation of these isoindolinones through Viedma ripening in ethanol.
Fig. 11 Selected conglomerate-forming chiral molecules that racemise differently in solution. pic is 3-picoline. |
trans-Succinimides undergo racemisation through the achiral cis-isomers which possess an intrinsic mirror plane (Fig. 11d).43 Starting with the achiral cis-isomer, desymmetrisation facilitated by DBU provides both enantiomers which rapidly racemise through the cis-isomer. In combination with conglomerate crystallisation, this resulted in total spontaneous resolution to give the products in quantitative yields and 85–98% ee.
In addition to chiral molecules, achiral molecules were recently obtained in enantiopure form through Viedma ripening. Of all achiral compounds, between 8 and 13% crystallise as conglomerate crystals. McLaughlin et al. applied Viedma ripening to deracemise ten achiral organic molecules that crystallise in a chiral fashion (three examples are shown in Fig. 12).44 Solid-state circular dichroism (CD) spectroscopy was used to determine the solid state ee.
Besides racemisation in solution, the formation of racemic conglomerate crystals is another prerequisite for reaching single chirality using the interplay between crystals and a solution. The synthesis of a library of derivatives is one approach to find conglomerate crystals. On the other hand, tailoring crystallisation processes can also open up possibilities that could enable the formation of additional examples of conglomerate crystals. This way, Spix et al. showed that a metastable conglomerate of glutamic acid can be deracemised through Viedma ripening (Fig. 13).45 Although glutamic acid forms a racemic compound in the form of a hydrate, it was found that a metastable conglomerate form can be obtained as the kinetic product in the presence of acetic acid. Racemisation of glutamic acid proceeds at elevated temperatures which also facilitates formation of two other unwanted racemic forms of the product. Therefore, experimental conditions were tweaked which ultimately enabled access to enantiopure glutamic acid in 80% yield through Viedma ripening starting from low initial ee's of 14%.
Alternatively, salt formation can be used as a tool to prepare a library of compounds which in turn could provide new conglomerate candidates. This way, Spix et al. combined six different amino acids with four different sulfonates resulting in twenty-four different salts.46 It was found that three out of the twenty-four salts (13%) were racemic conglomerate crystals. Although leucine-2,5-xylenesulfonate was unstable under the applied Viedma ripening conditions which involves the use of acetic acid, the two other conglomerates (i.e. alanine-4-chlorobenzenesulfonate in 35–42% yield and phenylalanine-2,5-xylenesulfonate in 60–63% yield) could be deracemised through Viedma ripening (Fig. 14). In all these cases, the yield is somewhat limited due to the solubility of the compounds.
While Viedma ripening found broad applicability, Viedma himself in collaboration with other groups found that deracemisation can be achieved through the use of a temperature gradient at high temperatures and without grinding.47,48 Coquerel et al. extended this observation to the use of deliberate ‘temperature cycling’ in order to gain a clearer picture of the mechanism behind this form of deracemisation, “of which the mechanism is still matter of debate”.49,50 With temperature cycling, all crystals start to dissolve simultaneously during a heating period, while the crystals remaining after the heating cycle are subsequently grown during the cooling period by consuming the excess of the solute molecules in the supersaturated solution (Fig. 15). A typical temperature program for temperature cycling involves rapid heating but slow cooling to avoid primary nucleation of the unwanted enantiomer. Such a program is repeated several times until an ee of 100% is reached.
Even though there still is no absolute consensus, recent mechanistic studies have provided a deeper understanding of the driving forces behind Viedma ripening. Most studies have shown that a feedback mechanism must be involved to account for the exponential increase in ee. This feedback mechanism can be explained in terms of chiral clusters which selectively incorporate into crystals of the same handedness. Despite some indirect experimental observations, undisputed evidence for chiral clusters remains to be revealed.
After the discovery of the traditional Viedma ripening method, many novel applications have been developed which enable the use of Viedma ripening on a large industrial scale as well as in synthetic organic chemistry. Also, attrition is no longer required as gentle temperature fluctuations can lead to solid-state deracemisation. Crystal-solution systems are also very useful in asymmetric autocatalysis as enantiopure compounds can be obtained from achiral reactants.
From this review it appears that to date many compounds are still obtained in enantiopure form through total spontaneous resolution instead of Viedma ripening. However, it should be noted that Viedma ripening is a more robust and reliable method as crystals of the unwanted enantiomer, which often prevent total spontaneous resolution from reaching an enantiopure end state, are transformed into the desired enantiomer. Although seeding is used in total spontaneous resolution to obtain the best results in terms of chiral purity of the final product, Viedma ripening leads to complete deracemisation without seeding, even when starting from a racemic mixture of crystals.
This journal is © The Royal Society of Chemistry 2015 |